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1
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Baran Z, Çetinkaya M, Baran Y. Mesenchymal Stem Cells in Cancer Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1474:149-177. [PMID: 39470980 DOI: 10.1007/5584_2024_824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/01/2024]
Abstract
The mesenchymal stem/stromal cells (MSCs) are multipotent cells that were initially discovered in the bone marrow in the late 1960s but have so far been discovered in almost all tissues of the body. The multipotent property of MSCs enables them to differentiate into various cell types and lineages, such as adipocytes, chondrocytes, and osteocytes. The immunomodulation capacity and tumor-targeting features of MSCs made their use crucial for cell-based therapies in cancer treatment, yet limited advancement could be observed in translational medicine prospects due to the need for more information regarding the controversial roles of MSCs in crosstalk tumors. In this review, we discuss the therapeutic potential of MSCs, the controversial roles played by MSCs in cancer progression, and the anticancer therapeutic strategies that are in association with MSCs. Finally, the clinical trials designed for the direct use of MSCs for cancer therapy or for their use in decreasing the side effects of other cancer therapies are also mentioned in this review to evaluate the current status of MSC-based cancer therapies.
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Affiliation(s)
- Züleyha Baran
- Laboratory of Molecular Pharmacology, Department of Pharmacology, Anadolu University, Eskişehir, Turkey
| | - Melisa Çetinkaya
- Laboratory of Cancer Genetics, Department of Molecular Biology and Genetics, İzmir Institute of Technology, İzmir, Turkey
| | - Yusuf Baran
- Laboratory of Cancer Genetics, Department of Molecular Biology and Genetics, İzmir Institute of Technology, İzmir, Turkey.
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2
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Kangari P, Salahlou R, Vandghanooni S. Harnessing the Therapeutic Potential of Mesenchymal Stem Cells in Cancer Treatment. Adv Pharm Bull 2024; 14:574-590. [PMID: 39494266 PMCID: PMC11530882 DOI: 10.34172/apb.2024.052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 06/12/2024] [Accepted: 06/19/2024] [Indexed: 11/05/2024] Open
Abstract
Cancer, as a complicated disease, is considered to be one of the major leading causes of death globally. Although various cancer therapeutic strategies have been established, however, some issues confine the efficacies of the treatments. In recent decades researchers for finding efficient therapeutic solutions have extensively focused on the abilities of stem cells in cancer inhibition. Mesenchymal stem cells (MSCs) are multipotent stromal cells that can the most widely extracted from various sources such as the bone marrow (BM), placenta, umbilical cord (UC), menses blood, Wharton's jelly (WJ), adipose tissue and dental pulp (DP). These cells are capable of differentiating into the osteoblasts, chondrocytes, and adipocytes. Due to the unique characteristics of MSCs such as paracrine effects, immunomodulation, tumor-tropism, and migration, they are considered promising candidates for cancer therapeutics. Currently, MSCs are an excellent living carrier for delivery of therapeutic genes and chemical agents to target tumor sites. Also, exosomes, the most important extracellular vesicle released from MSCs, act as a strong cell-free tool for cancer therapeutics. MSCs can prevent cancer progression by inhibiting several signaling pathways, such as wnt/β-catenin and PI3K/AKT/mTOR. However, there are several challenges associated with the use of MSCs and their exosomes in the field of therapy that need to be considered. This review explores the significance of MSCs in cell-based therapy, focusing on their homing properties and immunomodulatory characteristics. It also examines the potential of using MSCs as carriers for delivery of anticancer agents and their role in modulating the signal transduction pathways of cancer cells.
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Affiliation(s)
- Parisa Kangari
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Salahlou
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Somayeh Vandghanooni
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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3
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Garza Treviño EN, Quiroz Reyes AG, Delgado Gonzalez P, Rojas Murillo JA, Islas JF, Alonso SS, Gonzalez Villarreal CA. Applications of Modified Mesenchymal Stem Cells as Targeted Systems against Tumor Cells. Int J Mol Sci 2024; 25:7791. [PMID: 39063032 PMCID: PMC11276748 DOI: 10.3390/ijms25147791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 06/22/2024] [Accepted: 06/26/2024] [Indexed: 07/28/2024] Open
Abstract
Combined gene and cell therapy are promising strategies for cancer treatment. Given the complexity of cancer, several approaches are actively studied to fight this disease. Using mesenchymal stem cells (MSCs) has demonstrated dual antitumor and protumor effects as they exert massive immune/regulatory effects on the tissue microenvironment. MSCs have been widely investigated to exploit their antitumor target delivery system. They can be genetically modified to overexpress genes and selectively or more efficiently eliminate tumor cells. Current approaches tend to produce more effective and safer therapies using MSCs or derivatives; however, the effect achieved by engineered MSCs in solid tumors is still limited and depends on several factors such as the cell source, transgene, and tumor target. This review describes the progress of gene and cell therapy focused on MSCs as a cornerstone against solid tumors, addressing the different MSC-engineering methods that have been approached over decades of research. Furthermore, we summarize the main objectives of engineered MSCs against the most common cancers and discuss the challenges, limitations, risks, and advantages of targeted treatments combined with conventional ones.
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Affiliation(s)
- Elsa N. Garza Treviño
- Laboratorio de Terapia Celular, Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Av. Dr. José Eleuterio González 235, Monterrey 64460, Nuevo León, Mexico; (E.N.G.T.); (A.G.Q.R.); (P.D.G.); (J.A.R.M.); (J.F.I.)
| | - Adriana G. Quiroz Reyes
- Laboratorio de Terapia Celular, Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Av. Dr. José Eleuterio González 235, Monterrey 64460, Nuevo León, Mexico; (E.N.G.T.); (A.G.Q.R.); (P.D.G.); (J.A.R.M.); (J.F.I.)
| | - Paulina Delgado Gonzalez
- Laboratorio de Terapia Celular, Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Av. Dr. José Eleuterio González 235, Monterrey 64460, Nuevo León, Mexico; (E.N.G.T.); (A.G.Q.R.); (P.D.G.); (J.A.R.M.); (J.F.I.)
| | - Juan Antonio Rojas Murillo
- Laboratorio de Terapia Celular, Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Av. Dr. José Eleuterio González 235, Monterrey 64460, Nuevo León, Mexico; (E.N.G.T.); (A.G.Q.R.); (P.D.G.); (J.A.R.M.); (J.F.I.)
| | - Jose Francisco Islas
- Laboratorio de Terapia Celular, Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Av. Dr. José Eleuterio González 235, Monterrey 64460, Nuevo León, Mexico; (E.N.G.T.); (A.G.Q.R.); (P.D.G.); (J.A.R.M.); (J.F.I.)
| | - Santiago Saavedra Alonso
- Departamento de Ciencias Básicas, Vicerrectoría de Ciencias de la Salud, Universidad de Monterrey, Ignacio Morones Prieto 4500, Jesus M. Garza, San Pedro Garza García 66238, Nuevo León, Mexico
| | - Carlos A. Gonzalez Villarreal
- Departamento de Ciencias Básicas, Vicerrectoría de Ciencias de la Salud, Universidad de Monterrey, Ignacio Morones Prieto 4500, Jesus M. Garza, San Pedro Garza García 66238, Nuevo León, Mexico
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4
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Saadh MJ, Alhuthali HM, Gonzales Aníbal O, Asenjo-Alarcón JA, Younus DG, Alhili A, Adhab ZH, Alsalmi O, Gharib AF, Pecho RDC, Akhavan-Sigari R. Mesenchymal stem cells and their extracellular vesicles in urological cancers: Prostate, bladder, and kidney. Cell Biol Int 2024; 48:3-19. [PMID: 37947445 DOI: 10.1002/cbin.12098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 08/31/2023] [Accepted: 10/12/2023] [Indexed: 11/12/2023]
Abstract
Mesenchymal stem cells (MSCs) are recognized for their remarkable ability to differentiate into multiple cell types. They are also known to possess properties that can fight cancer, leading to attempts to modify MSCs for use in anticancer treatments. However, MSCs have also been found to participate in pathways that promote tumor growth. Many studies have been conducted to explore the potential of MSCs for clinical applications, but the results have been inconclusive, possibly due to the diverse nature of MSC populations. Furthermore, the conflicting roles of MSCs in inhibiting tumors and promoting tumor growth hinder their adaptation to anticancer therapies. Antitumorigenic and protumorigenic properties of MSCs in urological cancers such as bladder, prostate, and renal are not as well established, and data comparing them are still limited. MSCs hold significant promise as a vehicle for delivering anticancer agents and suicide genes to tumors. Presently, numerous studies have concentrated on the products derived from MSCs, such as extracellular vesicles (EVs), as a form of cell-free therapy. This work aimed to review and discuss the current knowledge of MSCs and their EVs in urological cancer therapy.
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Affiliation(s)
| | - Hayaa M Alhuthali
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | | | | | | | - Ahmed Alhili
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
| | | | - Ohud Alsalmi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | - Amal F Gharib
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | | | - Reza Akhavan-Sigari
- Department of Neurosurgery, University Medical Center Tuebingen, Tuebingen, Germany
- Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw Management University, Warsaw, Poland
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5
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Borzone FR, Giorello MB, Sanmartin MC, Yannarelli G, Martinez LM, Chasseing NA. Mesenchymal stem cells and cancer-associated fibroblasts as a therapeutic strategy for breast cancer. Br J Pharmacol 2024; 181:238-256. [PMID: 35485850 DOI: 10.1111/bph.15861] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 03/21/2022] [Accepted: 04/22/2022] [Indexed: 11/26/2022] Open
Abstract
Breast cancer is the most common type of cancer and the leading cause of death among women. Recent evidence suggests that mesenchymal stromal/stem cells and cancer-associated fibroblasts (CAFs) have an essential role in cancer progression, invasion and therapy resistance. Therefore, they are considered as highly promising future therapeutic targets against breast cancer. The intrinsic tumour tropism and immunomodulatory capacities of mesenchymal stromal/stem cells are of special relevance for developing mesenchymal stromal/stem cells-based anti-tumour therapies that suppress primary tumour growth and metastasis. In addition, the utilization of therapies that target the stromal components of the tumour microenvironment in combination with standard drugs is an innovative tool that could improve patients' response to therapies and their survival. In this review, we discuss the currently available information regarding the possible use of mesenchymal stromal/stem cells-derived anti-tumour therapies, as well as the utilization of therapies that target CAFs in breast cancer microenvironment. Finally, these data can serve as a guide map for future research in this field, ultimately aiding the effective transition of these results into the clinic. LINKED ARTICLES: This article is part of a themed issue on Cancer Microenvironment and Pharmacological Interventions. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.2/issuetoc.
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Affiliation(s)
- Francisco Raúl Borzone
- Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - María Belén Giorello
- Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - María Cecilia Sanmartin
- Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
- Laboratorio de Regulación Génica y Células Madre, Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMeTTyB), Universidad Favaloro-CONICET, Buenos Aires, Argentina
| | - Gustavo Yannarelli
- Laboratorio de Regulación Génica y Células Madre, Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMeTTyB), Universidad Favaloro-CONICET, Buenos Aires, Argentina
| | - Leandro Marcelo Martinez
- Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA
| | - Norma Alejandra Chasseing
- Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
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Rosu A, Ghaemi B, Bulte JW, Shakeri-Zadeh A. Tumor-tropic Trojan horses: Using mesenchymal stem cells as cellular nanotheranostics. Theranostics 2024; 14:571-591. [PMID: 38169524 PMCID: PMC10758060 DOI: 10.7150/thno.90187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 11/21/2023] [Indexed: 01/05/2024] Open
Abstract
Various classes of nanotheranostics have been developed for enhanced tumor imaging and therapy. However, key limitations for a successful use of nanotheranostics include their targeting specificity with limited off-site tissue accumulation as well as their distribution and prolonged retention throughout the entire tumor. Due to their inherent tumor-tropic properties, the use of mesenchymal stem cells (MSCs) as a "Trojan horse" has recently been proposed to deliver nanotheranostics more effectively. This review discusses the current status of "cellular nanotheranostics" for combined (multimodal) imaging and therapy in preclinical cancer models. Emphasis is placed on the limited knowledge of the signaling pathways and molecular mechanisms of MSC tumor-tropism, and how such information may be exploited to engineer MSCs in order to further improve tumor homing and nanotheranostic delivery using image-guided procedures.
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Affiliation(s)
| | | | | | - Ali Shakeri-Zadeh
- The Russell H. Morgan Department of Radiology and Radiological Science, Division of MR Research and Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Bashyal N, Kim MG, Jung JH, Acharya R, Lee YJ, Hwang WS, Choi JM, Chang DY, Kim SS, Suh-Kim H. Preclinical Study on Biodistribution of Mesenchymal Stem Cells after Local Transplantation into the Brain. Int J Stem Cells 2023; 16:415-424. [PMID: 37643762 PMCID: PMC10686801 DOI: 10.15283/ijsc23062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 06/07/2023] [Accepted: 06/07/2023] [Indexed: 08/31/2023] Open
Abstract
Therapeutic efficacy of mesenchymal stem cells (MSCs) is determined by biodistribution and engraftment in vivo. Compared to intravenous infusion, biodistribution of locally transplanted MSCs are partially understood. Here, we performed a pharmacokinetics (PK) study of MSCs after local transplantation. We grafted human MSCs into the brains of immune-compromised nude mice. Then we extracted genomic DNA from brains, lungs, and livers after transplantation over a month. Using quantitative polymerase chain reaction with human Alu-specific primers, we analyzed biodistribution of the transplanted cells. To evaluate the role of residual immune response in the brain, MSCs expressing a cytosine deaminase (MSCs/CD) were used to ablate resident immune cells at the injection site. The majority of the Alu signals mostly remained at the injection site and decreased over a week, finally becoming undetectable after one month. Negligible signals were transiently detected in the lung and liver during the first week. Suppression of Iba1-positive microglia in the vicinity of the injection site using MSCs/CD prolonged the presence of the Alu signals. After local transplantation in xenograft animal models, human MSCs remain predominantly near the injection site for limited time without disseminating to other organs. Transplantation of human MSCs can locally elicit an immune response in immune compromised animals, and suppressing resident immune cells can prolong the presence of transplanted cells. Our study provides valuable insights into the in vivo fate of locally transplanted stem cells and a local delivery is effective to achieve desired dosages for neurological diseases.
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Affiliation(s)
| | - Min Gyeong Kim
- Department of Anatomy, Ajou University School of Medicine, Suwon, Korea
- Department of Biomedical Sciences, Graduate School, Ajou University School of Medicine, Suwon, Korea
| | - Jin-Hwa Jung
- Research Center, CELLeBRAIN, Ltd., Jeonju, Korea
| | - Rakshya Acharya
- Department of Anatomy, Ajou University School of Medicine, Suwon, Korea
| | - Young Jun Lee
- Department of Anatomy, Ajou University School of Medicine, Suwon, Korea
- Department of Biomedical Sciences, Graduate School, Ajou University School of Medicine, Suwon, Korea
| | - Woo Sup Hwang
- Department of Anatomy, Ajou University School of Medicine, Suwon, Korea
| | - Jung-Mi Choi
- Department of Anatomy, Ajou University School of Medicine, Suwon, Korea
| | | | - Sung-Soo Kim
- Department of Anatomy, Ajou University School of Medicine, Suwon, Korea
| | - Haeyoung Suh-Kim
- Research Center, CELLeBRAIN, Ltd., Jeonju, Korea
- Department of Anatomy, Ajou University School of Medicine, Suwon, Korea
- Department of Biomedical Sciences, Graduate School, Ajou University School of Medicine, Suwon, Korea
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Shams F, Pourjabbar B, Hashemi N, Farahmandian N, Golchin A, Nuoroozi G, Rahimpour A. Current progress in engineered and nano-engineered mesenchymal stem cells for cancer: From mechanisms to therapy. Biomed Pharmacother 2023; 167:115505. [PMID: 37716113 DOI: 10.1016/j.biopha.2023.115505] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 09/11/2023] [Accepted: 09/12/2023] [Indexed: 09/18/2023] Open
Abstract
Mesenchymal stem cells (MSCs), as self-renewing multipotent stromal cells, have been considered promising agents for cancer treatment. A large number of studies have demonstrated the valuable properties of MSC-based treatment, such as low immunogenicity and intrinsic tumor-trophic migratory properties. To enhance the potency of MSCs for therapeutic purposes, equipping MSCs with targeted delivery functions using genetic engineering is highly beneficial. Genetically engineered MSCs can express tumor suppressor agents such as pro-apoptotic, anti-proliferative, anti-angiogenic factors and act as ideal delivery vehicles. MSCs can also be loaded with nanoparticle drugs for increased efficacy and externally moderated targeting. Moreover, exosomes secreted by MSCs have important physiological properties, so they can contribute to intercellular communication and transfer cargo into targeted tumor cells. The precise role of genetically modified MSCs in tumor environments is still up for debate, but the beginning of clinical trials has been confirmed by promising results from preclinical investigations of MSC-based gene therapy for a wide range of malignancies. This review highlights the advanced techniques of engineering/nano-engineering and MSC-derived exosomes in tumor-targeted therapy.
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Affiliation(s)
- Forough Shams
- Student Research Committee, Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, 1968917313 Tehran, Iran
| | - Bahareh Pourjabbar
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nader Hashemi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, 1968917313 Tehran, Iran
| | - Navid Farahmandian
- Department of Tissue Engineering & Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Golchin
- Cellular & Molecular Research Center, Cellular & Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia 57157993313, Iran; Department of Clinical Biochemistry & Applied Cell Sciences, School of Medicine, Urmia University of Medical Sciences, Urmia 57157993313, Islamic Republic of Iran
| | - Ghader Nuoroozi
- Men's Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Azam Rahimpour
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Afkhami H, Mahmoudvand G, Fakouri A, Shadab A, Mahjoor M, Komeili Movahhed T. New insights in application of mesenchymal stem cells therapy in tumor microenvironment: pros and cons. Front Cell Dev Biol 2023; 11:1255697. [PMID: 37849741 PMCID: PMC10577325 DOI: 10.3389/fcell.2023.1255697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Accepted: 09/11/2023] [Indexed: 10/19/2023] Open
Abstract
Multipotent mesenchymal stem cells (MSCs) are widely accepted as a useful tool for cell-based therapy of various diseases including malignancies. The therapeutic effects of MSCs are mainly attributed to their immunomodulatory and immunosuppressive properties. Despite the promising outcomes of MSCs in cancer therapy, a growing body of evidence implies that MSCs also show tumorigenic properties in the tumor microenvironment (TME), which might lead to tumor induction and progression. Owing to the broad-spectrum applications of MSCs, this challenge needs to be tackled so that they can be safely utilized in clinical practice. Herein, we review the diverse activities of MSCs in TME and highlight the potential methods to convert their protumorigenic characteristics into onco-suppressive effects.
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Affiliation(s)
- Hamed Afkhami
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
| | - Golnaz Mahmoudvand
- Student Research Committee, USERN Office, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Arshia Fakouri
- Student Research Committee, USERN Office, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Alireza Shadab
- Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
- Iran University of Medical Sciences, Deputy of Health, Tehran, Iran
| | - Mohamad Mahjoor
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
- Department of Immunology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
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Zhao Y, Shen M, Wu L, Yang H, Yao Y, Yang Q, Du J, Liu L, Li Y, Bai Y. Stromal cells in the tumor microenvironment: accomplices of tumor progression? Cell Death Dis 2023; 14:587. [PMID: 37666813 PMCID: PMC10477351 DOI: 10.1038/s41419-023-06110-6] [Citation(s) in RCA: 135] [Impact Index Per Article: 67.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Revised: 08/17/2023] [Accepted: 08/22/2023] [Indexed: 09/06/2023]
Abstract
The tumor microenvironment (TME) is made up of cells and extracellular matrix (non-cellular component), and cellular components include cancer cells and non-malignant cells such as immune cells and stromal cells. These three types of cells establish complex signals in the body and further influence tumor genesis, development, metastasis and participate in resistance to anti-tumor therapy. It has attracted scholars to study immune cells in TME due to the significant efficacy of immune checkpoint inhibitors (ICI) and chimeric antigen receptor T (CAR-T) in solid tumors and hematologic tumors. After more than 10 years of efforts, the role of immune cells in TME and the strategy of treating tumors based on immune cells have developed rapidly. Moreover, ICI have been recommended by guidelines as first- or second-line treatment strategies in a variety of tumors. At the same time, stromal cells is another major class of cellular components in TME, which also play a very important role in tumor metabolism, growth, metastasis, immune evasion and treatment resistance. Stromal cells can be recruited from neighboring non-cancerous host stromal cells and can also be formed by transdifferentiation from stromal cells to stromal cells or from tumor cells to stromal cells. Moreover, they participate in tumor genesis, development and drug resistance by secreting various factors and exosomes, participating in tumor angiogenesis and tumor metabolism, regulating the immune response in TME and extracellular matrix. However, with the deepening understanding of stromal cells, people found that stromal cells not only have the effect of promoting tumor but also can inhibit tumor in some cases. In this review, we will introduce the origin of stromal cells in TME as well as the role and specific mechanism of stromal cells in tumorigenesis and tumor development and strategies for treatment of tumors based on stromal cells. We will focus on tumor-associated fibroblasts (CAFs), mesenchymal stem cells (MSCs), tumor-associated adipocytes (CAAs), tumor endothelial cells (TECs) and pericytes (PCs) in stromal cells.
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Affiliation(s)
- Yan Zhao
- Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University, 130033, Changchun, Jilin, China
| | - Meili Shen
- Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, 130033, Changchun, Jilin, China
| | - Liangqiang Wu
- Key Laboratory of Special Engineering Plastics Ministry of Education, College of Chemistry, Jilin University, 130012, Changchun, Jilin, China
| | - Haiqin Yang
- Key Laboratory of Special Engineering Plastics Ministry of Education, College of Chemistry, Jilin University, 130012, Changchun, Jilin, China
| | - Yixuan Yao
- Key Laboratory of Special Engineering Plastics Ministry of Education, College of Chemistry, Jilin University, 130012, Changchun, Jilin, China
| | - Qingbiao Yang
- Key Laboratory of Special Engineering Plastics Ministry of Education, College of Chemistry, Jilin University, 130012, Changchun, Jilin, China
| | - Jianshi Du
- Key Laboratory of Lymphatic Surgery Jilin Province, Jilin Engineering Laboratory for Lymphatic Surgery Jilin Province, China-Japan Union Hospital of Jilin University, 130033, Changchun, Jilin, China
| | - Linlin Liu
- Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, 130033, Changchun, Jilin, China
| | - Yapeng Li
- Key Laboratory of Special Engineering Plastics Ministry of Education, College of Chemistry, Jilin University, 130012, Changchun, Jilin, China.
| | - Yuansong Bai
- Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University, 130033, Changchun, Jilin, China.
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11
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Ghaleh HEG, Vakilzadeh G, Zahiri A, Farzanehpour M. Investigating the potential of oncolytic viruses for cancer treatment via MSC delivery. Cell Commun Signal 2023; 21:228. [PMID: 37667271 PMCID: PMC10478302 DOI: 10.1186/s12964-023-01232-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 07/16/2023] [Indexed: 09/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have attracted considerable interest as a promising approach for cancer treatment due to their ability to undergo tumor-trophic migration. MSCs possess the unique ability to selectively migrate to tumors, making them an excellent candidate for targeted delivery of oncolytic viruses (OVs) to treat isolated tumors and metastatic malignancies. OVs have attracted attention as a potential treatment for cancer due to their ability to selectively infect and destroy tumor cells while sparing normal cells. In addition, OVs can induce immunogenic cell death and contain curative transgenes in their genome, making them an attractive candidate for cancer treatment in combination with immunotherapies. In combination with MSCs, OVs can modulate the tumor microenvironment and trigger anti-tumor immune responses, making MSC-releasing OVs a promising approach for cancer treatment. This study reviews researches on the use of MSC-released OVs as a novel method for treating cancer. Video Abstract.
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Affiliation(s)
| | - Gazal Vakilzadeh
- Applied Virology Research Center, Baqiyatallah University of Medical sciences, Tehran, Iran
| | - Ali Zahiri
- Students Research Committee, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Mahdieh Farzanehpour
- Applied Virology Research Center, Baqiyatallah University of Medical sciences, Tehran, Iran.
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12
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Slama Y, Ah-Pine F, Khettab M, Arcambal A, Begue M, Dutheil F, Gasque P. The Dual Role of Mesenchymal Stem Cells in Cancer Pathophysiology: Pro-Tumorigenic Effects versus Therapeutic Potential. Int J Mol Sci 2023; 24:13511. [PMID: 37686315 PMCID: PMC10488262 DOI: 10.3390/ijms241713511] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 08/29/2023] [Accepted: 08/30/2023] [Indexed: 09/10/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are multipotent cells involved in numerous physiological events, including organogenesis, the maintenance of tissue homeostasis, regeneration, or tissue repair. MSCs are increasingly recognized as playing a major, dual, and complex role in cancer pathophysiology through their ability to limit or promote tumor progression. Indeed, these cells are known to interact with the tumor microenvironment, modulate the behavior of tumor cells, influence their functions, and promote distant metastasis formation through the secretion of mediators, the regulation of cell-cell interactions, and the modulation of the immune response. This dynamic network can lead to the establishment of immunoprivileged tissue niches or the formation of new tumors through the proliferation/differentiation of MSCs into cancer-associated fibroblasts as well as cancer stem cells. However, MSCs exhibit also therapeutic effects including anti-tumor, anti-proliferative, anti-inflammatory, or anti-oxidative effects. The therapeutic interest in MSCs is currently growing, mainly due to their ability to selectively migrate and penetrate tumor sites, which would make them relevant as vectors for advanced therapies. Therefore, this review aims to provide an overview of the double-edged sword implications of MSCs in tumor processes. The therapeutic potential of MSCs will be reviewed in melanoma and lung cancers.
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Affiliation(s)
- Youssef Slama
- Unité de Recherche Études Pharmaco-Immunologiques (EPI), Université de La Réunion, CHU de La Réunion, Allée des Topazes, 97400 Saint-Denis, La Réunion, France; (F.A.-P.); (M.K.); (P.G.)
- Service de Radiothérapie, Clinique Sainte-Clotilde, Groupe Clinifutur, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France; (M.B.); (F.D.)
- Laboratoire Interdisciplinaire de Recherche en Santé (LIRS), RunResearch, Clinique Sainte-Clotilde, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France;
| | - Franck Ah-Pine
- Unité de Recherche Études Pharmaco-Immunologiques (EPI), Université de La Réunion, CHU de La Réunion, Allée des Topazes, 97400 Saint-Denis, La Réunion, France; (F.A.-P.); (M.K.); (P.G.)
- Service d’Anatomie et Cytologie Pathologiques, CHU de La Réunion sites SUD—Saint-Pierre, Avenue François Mitterrand, 97448 Saint-Pierre Cedex, La Réunion, France
| | - Mohamed Khettab
- Unité de Recherche Études Pharmaco-Immunologiques (EPI), Université de La Réunion, CHU de La Réunion, Allée des Topazes, 97400 Saint-Denis, La Réunion, France; (F.A.-P.); (M.K.); (P.G.)
- Service d’Oncologie Médicale, CHU de La Réunion sites SUD—Saint-Pierre, Avenue François Mitterrand, 97448 Saint-Pierre Cedex, La Réunion, France
| | - Angelique Arcambal
- Laboratoire Interdisciplinaire de Recherche en Santé (LIRS), RunResearch, Clinique Sainte-Clotilde, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France;
| | - Mickael Begue
- Service de Radiothérapie, Clinique Sainte-Clotilde, Groupe Clinifutur, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France; (M.B.); (F.D.)
- Laboratoire Interdisciplinaire de Recherche en Santé (LIRS), RunResearch, Clinique Sainte-Clotilde, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France;
| | - Fabien Dutheil
- Service de Radiothérapie, Clinique Sainte-Clotilde, Groupe Clinifutur, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France; (M.B.); (F.D.)
- Laboratoire Interdisciplinaire de Recherche en Santé (LIRS), RunResearch, Clinique Sainte-Clotilde, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France;
| | - Philippe Gasque
- Unité de Recherche Études Pharmaco-Immunologiques (EPI), Université de La Réunion, CHU de La Réunion, Allée des Topazes, 97400 Saint-Denis, La Réunion, France; (F.A.-P.); (M.K.); (P.G.)
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Karami Fath M, Moayedi Banan Z, Barati R, Mohammadrezakhani O, Ghaderi A, Hatami A, Ghiabi S, Zeidi N, Asgari K, Payandeh Z, Barati G. Recent advancements to engineer mesenchymal stem cells and their extracellular vesicles for targeting and destroying tumors. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2023; 178:1-16. [PMID: 36781149 DOI: 10.1016/j.pbiomolbio.2023.02.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 01/24/2023] [Accepted: 02/10/2023] [Indexed: 02/13/2023]
Abstract
Mesenchymal stem cells (MSCs) have the ability to migrate into tumor sites and release growth factors to modulate the tumor microenvironment. MSC therapy have shown a dual role in cancers, promoting or inhibiting. However, MSCs could be used as a carrier of anticancer agents for targeted tumor therapy. Recent technical improvements also allow engineering MSCs to improve tumor-targeting properties, protect anticancer agents, and decrease the cytotoxicity of drugs. While some of MSC functions are mediated through their secretome, MSCs-derived extracellular vesicles (EVs) are also proposed as a possible viechle for cancer therapy. EVs allow efficient loading of anticancer agents and have an intrinsic ability to target tumor cells, making them suitable for targeted therapy of tumors. In addition, the specificity and selectivity of EVs to the tumor sites could be enhanced by surface modification. In this review, we addressed the current approaches used for engineering MSCs and EVs to effectively target tumor sites and deliver anticancer agents.
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Affiliation(s)
- Mohsen Karami Fath
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Zahra Moayedi Banan
- School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Reza Barati
- School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Omid Mohammadrezakhani
- Faculty of Pharmacy, Ramsar Campus, Mazandaran University of Medical Sciences, Sari, Iran
| | - Aliasghar Ghaderi
- Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Hatami
- School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shamim Ghiabi
- Department of Medical Chemistry, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Nazanin Zeidi
- Division of Pharmaceutical Science, Long Island University, Brooklyn, NY, USA
| | - Katayoon Asgari
- Department of Clinical Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Payandeh
- Department Medical Biochemistry and Biophysics, Division Medical Inflammation Research, Karolinska Institute, Stockholm, Sweden
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14
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Ghasemi Darestani N, Gilmanova AI, Al-Gazally ME, Zekiy AO, Ansari MJ, Zabibah RS, Jawad MA, Al-Shalah SAJ, Rizaev JA, Alnassar YS, Mohammed NM, Mustafa YF, Darvishi M, Akhavan-Sigari R. Mesenchymal stem cell-released oncolytic virus: an innovative strategy for cancer treatment. Cell Commun Signal 2023; 21:43. [PMID: 36829187 PMCID: PMC9960453 DOI: 10.1186/s12964-022-01012-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 12/10/2022] [Indexed: 02/26/2023] Open
Abstract
Oncolytic viruses (OVs) infect, multiply, and finally remove tumor cells selectively, causing no damage to normal cells in the process. Because of their specific features, such as, the ability to induce immunogenic cell death and to contain curative transgenes in their genomes, OVs have attracted attention as candidates to be utilized in cooperation with immunotherapies for cancer treatment. This treatment takes advantage of most tumor cells' inherent tendency to be infected by certain OVs and both innate and adaptive immune responses are elicited by OV infection and oncolysis. OVs can also modulate tumor microenvironment and boost anti-tumor immune responses. Mesenchymal stem cells (MSC) are gathering interest as promising anti-cancer treatments with the ability to address a wide range of cancers. MSCs exhibit tumor-trophic migration characteristics, allowing them to be used as delivery vehicles for successful, targeted treatment of isolated tumors and metastatic malignancies. Preclinical and clinical research were reviewed in this study to discuss using MSC-released OVs as a novel method for the treatment of cancer. Video Abstract.
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Affiliation(s)
| | - Anna I Gilmanova
- Department of Prosthetic Dentistry of the I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation
| | | | - Angelina O Zekiy
- Department of Prosthetic Dentistry of the I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation
| | - Mohammad Javed Ansari
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | | | - Saif A J Al-Shalah
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, Babylon, Iraq
| | - Jasur Alimdjanovich Rizaev
- Department of Public Health and Healthcare Management, Rector, Samarkand State Medical University, Samarkand, Uzbekistan
| | | | | | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | - Mohammad Darvishi
- Department of Aerospace and Subaquatic Medicine, Infectious Diseases and Tropical Medicine Research Center (IDTMRC), AJA University of Medical Sciences, Tehran, Iran.
| | - Reza Akhavan-Sigari
- Department of Neurosurgery, University Medical Center, Tuebingen, Germany.,Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw Management University, Warsaw, Poland
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15
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Dai X, Zhu K. Cold atmospheric plasma: Novel opportunities for tumor microenvironment targeting. Cancer Med 2023; 12:7189-7206. [PMID: 36762766 PMCID: PMC10067048 DOI: 10.1002/cam4.5491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 07/17/2022] [Accepted: 11/17/2022] [Indexed: 02/11/2023] Open
Abstract
With mounting preclinical and clinical evidences on the prominent roles of the tumor microenvironment (TME) played during carcinogenesis, the TME has been recognized and used as an important onco-therapeutic target during the past decade. Delineating our current knowledge on TME components and their functionalities can help us recognize novel onco-therapeutic opportunities and establish treatment modalities towards desirable anti-cancer outcome. By identifying and focusing on primary cellular components in the TME, that is, tumor-infiltrating lymphocytes, tumor-associated macrophages, cancer-associated fibroblasts and mesenchymal stem cells, we decomposed their primary functionalities during carcinogenesis, categorized current therapeutic approaches utilizing traits of these components, and forecasted possible benefits that cold atmospheric plasma, a redox modulating tool with selectivity against cancer cells, may convey by targeting the TME. Our insights may open a novel therapeutic avenue for cancer control taking advantages of redox homeostasis and immunostasis.
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Affiliation(s)
- Xiaofeng Dai
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Kaiyuan Zhu
- Affiliated Hospital of Jiangnan University, Wuxi, China
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16
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Braatz D, Cherri M, Tully M, Dimde M, Ma G, Mohammadifar E, Reisbeck F, Ahmadi V, Schirner M, Haag R. Chemical Approaches to Synthetic Drug Delivery Systems for Systemic Applications. Angew Chem Int Ed Engl 2022; 61:e202203942. [PMID: 35575255 PMCID: PMC10091760 DOI: 10.1002/anie.202203942] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Indexed: 11/10/2022]
Abstract
Poor water solubility and low bioavailability of active pharmaceutical ingredients (APIs) are major causes of friction in the pharmaceutical industry and represent a formidable hurdle for pharmaceutical drug development. Drug delivery remains the major challenge for the application of new small-molecule drugs as well as biopharmaceuticals. The three challenges for synthetic delivery systems are: (i) controlling drug distribution and clearance in the blood; (ii) solubilizing poorly water-soluble agents, and (iii) selectively targeting specific tissues. Although several polymer-based systems have addressed the first two demands and have been translated into clinical practice, no targeted synthetic drug delivery system has reached the market. This Review is designed to provide a background on the challenges and requirements for the design and translation of new polymer-based delivery systems. This report will focus on chemical approaches to drug delivery for systemic applications.
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Affiliation(s)
- Daniel Braatz
- Institute of Chemistry and BiochemistryFreie Universität BerlinTakustr. 314195BerlinGermany
| | - Mariam Cherri
- Institute of Chemistry and BiochemistryFreie Universität BerlinTakustr. 314195BerlinGermany
| | - Michael Tully
- Institute of Chemistry and BiochemistryFreie Universität BerlinTakustr. 314195BerlinGermany
| | - Mathias Dimde
- Institute of Chemistry and BiochemistryFreie Universität BerlinTakustr. 314195BerlinGermany
| | - Guoxin Ma
- Institute of Chemistry and BiochemistryFreie Universität BerlinTakustr. 314195BerlinGermany
| | - Ehsan Mohammadifar
- Institute of Chemistry and BiochemistryFreie Universität BerlinTakustr. 314195BerlinGermany
| | - Felix Reisbeck
- Institute of Chemistry and BiochemistryFreie Universität BerlinTakustr. 314195BerlinGermany
| | - Vahid Ahmadi
- Institute of Chemistry and BiochemistryFreie Universität BerlinTakustr. 314195BerlinGermany
| | - Michael Schirner
- Institute of Chemistry and BiochemistryFreie Universität BerlinTakustr. 314195BerlinGermany
| | - Rainer Haag
- Institute of Chemistry and BiochemistryFreie Universität BerlinTakustr. 314195BerlinGermany
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17
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Wang Y, Fang J, Liu B, Shao C, Shi Y. Reciprocal regulation of mesenchymal stem cells and immune responses. Cell Stem Cell 2022; 29:1515-1530. [DOI: 10.1016/j.stem.2022.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/19/2022] [Accepted: 10/04/2022] [Indexed: 11/06/2022]
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18
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Prostate Cancer Tumor Stroma: Responsibility in Tumor Biology, Diagnosis and Treatment. Cancers (Basel) 2022; 14:cancers14184412. [PMID: 36139572 PMCID: PMC9496870 DOI: 10.3390/cancers14184412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 09/05/2022] [Accepted: 09/06/2022] [Indexed: 12/24/2022] Open
Abstract
Simple Summary The crosstalk between prostate stroma and its epithelium is essential to tissue homeostasis. Likewise, reciprocal signaling between tumor cells and the stromal compartment is required in tumor progression to facilitate or stimulate key processes such as cell proliferation and invasion. The aim of the present work was to review the current state of knowledge on the significance of tumor stroma in the genesis, progression and therapeutic response of prostate carcinoma. Additionally, we addressed the future therapeutic opportunities. Abstract Prostate cancer (PCa) is a common cancer among males globally, and its occurrence is growing worldwide. Clinical decisions about the combination of therapies are becoming highly relevant. However, this is a heterogeneous disease, ranging widely in prognosis. Therefore, new approaches are needed based on tumor biology, from which further prognostic assessments can be established and complementary strategies can be identified. The knowledge of both the morphological structure and functional biology of the PCa stroma compartment can provide new diagnostic, prognostic or therapeutic possibilities. In the present review, we analyzed the aspects related to the tumor stromal component (both acellular and cellular) in PCa, their influence on tumor behavior and the therapeutic response and their consideration as a new therapeutic target.
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19
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Rahimi Tesiye M, Abrishami Kia Z, Rajabi-Maham H. Mesenchymal stem cells and prostate cancer: A concise review of therapeutic potentials and biological aspects. Stem Cell Res 2022; 63:102864. [PMID: 35878578 DOI: 10.1016/j.scr.2022.102864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 07/06/2022] [Accepted: 07/08/2022] [Indexed: 11/09/2022] Open
Abstract
Prostate cancer (PCa) arises from a cancer stem or progenitor cell with homogenous characteristics, especially among the aging men population. Over the past decade, the increasing PCa incidence has led to significant changes in both disease diagnosis and treatment. Recently, the therapeutic aspects of stem cells in many cancers, including PCa, have been debatable. The new generation of PCa studies seek to present definitive treatments with reduced therapeutic side effects. Since discovering unique properties of stem cells in modulating immunity, selective migration to inflammatory regions, and secretion of various growth factors, they have been a promising therapeutic target. The existing properties of stem cell therapy bring new opportunities for cancer inhibition: transferring chemotherapeutics, activating prodrugs, affecting the expression of genes involved in cancer, genetically modifying the production of anti-cancer compounds, proteins, and/or deriving extracellular vesicles (EVs) containing therapeutic agents from stem cells. However, their dual properties in carcinogenicity as well as their ability to inhibit cancer result in particular limitations studying them after administration. A clear understanding of the interaction between MSCs and the prostate cancer microenvironment will provide crucial information in revealing the precise applications and new practical protocols for clinical use of these cells..
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Affiliation(s)
- Maryam Rahimi Tesiye
- Faculty of Life Science and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Zahra Abrishami Kia
- Faculty of Physical Education and Sport Sciences, University of Mazandaran, Babolsar, Iran.
| | - Hassan Rajabi-Maham
- Faculty of Life Science and Biotechnology, Shahid Beheshti University, Tehran, Iran
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20
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Mesenchymal stem cells: A living carrier for active tumor-targeted delivery. Adv Drug Deliv Rev 2022; 185:114300. [PMID: 35447165 DOI: 10.1016/j.addr.2022.114300] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 03/22/2022] [Accepted: 04/12/2022] [Indexed: 12/16/2022]
Abstract
The strategy of using mesenchymal stem cells (MSCs) as a living carrier for active delivery of therapeutic agents targeting tumor sites has been attempted in a wide range of studies to validate the feasibility and efficacy for tumor treatment. This approach reveals powerful tumor targeting and tumor penetration. In addition, MSCs have been confirmed to actively participate in immunomodulation of the tumor microenvironment. Thus, MSCs are not inert delivery vehicles but have a strong impact on the fate of tumor cells. In this review, these active properties of MSCs are addressed to highlight the advantages and challenges of using MSCs for tumor-targeted delivery. In addition, some of the latest examples of using MSCs to carry a variety of anti-tumor agents for tumor-targeted therapy are summarized. Recent technologies to improve the performance and safety of this delivery strategy will be introduced. The advances, applications, and challenges summarized in this review will provide a general understanding of this promising strategy for actively delivering drugs to tumor tissues.
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21
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Szewc M, Radzikowska-Bűchner E, Wdowiak P, Kozak J, Kuszta P, Niezabitowska E, Matysiak J, Kubiński K, Masłyk M. MSCs as Tumor-Specific Vectors for the Delivery of Anticancer Agents-A Potential Therapeutic Strategy in Cancer Diseases: Perspectives for Quinazoline Derivatives. Int J Mol Sci 2022; 23:2745. [PMID: 35269887 PMCID: PMC8911180 DOI: 10.3390/ijms23052745] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/23/2022] [Accepted: 02/28/2022] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are considered to be a powerful tool in the treatment of various diseases. Scientists are particularly interested in the possibility of using MSCs in cancer therapy. The research carried out so far has shown that MSCs possess both potential pro-oncogenic and anti-oncogenic properties. It has been confirmed that MSCs can regulate tumor cell growth through a paracrine mechanism, and molecules secreted by MSCs can promote or block a variety of signaling pathways. These findings may be crucial in the development of new MSC-based cell therapeutic strategies. The abilities of MSCs such as tumor tropism, deep migration and immune evasion have evoked considerable interest in their use as tumor-specific vectors for small-molecule anticancer agents. Studies have shown that MSCs can be successfully loaded with chemotherapeutic drugs such as gemcitabine and paclitaxel, and can release them at the site of primary and metastatic neoplasms. The inhibitory effect of MSCs loaded with anti-cancer agents on the proliferation of cancer cells has also been observed. However, not all known chemotherapeutic agents can be used in this approach, mainly due to their cytotoxicity towards MSCs and insufficient loading and release capacity. Quinazoline derivatives appear to be an attractive choice for this therapeutic solution due to their biological and pharmacological properties. There are several quinazolines that have been approved for clinical use as anticancer drugs by the US Food and Drug Administration (FDA). It gives hope that the synthesis of new quinazoline derivatives and the development of methods of their application may contribute to the establishment of highly effective therapies for oncological patients. However, a deeper understanding of interactions between MSCs and tumor cells, and the exploration of the possibilities of using quinazoline derivatives in MSC-based therapy is necessary to achieve this goal. The aim of this review is to discuss the prospects for using MSC-based cell therapy in cancer treatment and the potential use of quinazolines in this procedure.
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Affiliation(s)
- Monika Szewc
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (P.W.); (J.K.); (P.K.)
| | - Elżbieta Radzikowska-Bűchner
- Department of Plastic, Reconstructive and Maxillary Surgery, Central Clinical Hospital MSWiA, 02-507 Warsaw, Poland;
| | - Paulina Wdowiak
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (P.W.); (J.K.); (P.K.)
| | - Joanna Kozak
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (P.W.); (J.K.); (P.K.)
| | - Piotr Kuszta
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (P.W.); (J.K.); (P.K.)
| | - Ewa Niezabitowska
- Department of Urology and Urological Oncology, Multidisciplinary Hospital in Lublin, 20-400 Lublin, Poland;
| | - Joanna Matysiak
- Department of Chemistry, University of Life Sciences in Lublin, 20-950 Lublin, Poland;
| | - Konrad Kubiński
- Department of Molecular Biology, The John Paul II Catholic University of Lublin, 20-708 Lublin, Poland;
| | - Maciej Masłyk
- Department of Molecular Biology, The John Paul II Catholic University of Lublin, 20-708 Lublin, Poland;
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22
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Tibensky M, Jakubechova J, Altanerova U, Pastorakova A, Rychly B, Baciak L, Mravec B, Altaner C. Gene-Directed Enzyme/Prodrug Therapy of Rat Brain Tumor Mediated by Human Mesenchymal Stem Cell Suicide Gene Extracellular Vesicles In Vitro and In Vivo. Cancers (Basel) 2022; 14:cancers14030735. [PMID: 35159002 PMCID: PMC8833758 DOI: 10.3390/cancers14030735] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 01/27/2022] [Accepted: 01/28/2022] [Indexed: 01/14/2023] Open
Abstract
Simple Summary Extracellular vesicles— exosomes—secreted by human mesenchymal stem/stromal cells are able to cross the blood–brain barrier and internalize glioblastoma cells. We prepared exosomes possessing a gene message, the product of which is able to convert nontoxic 5-fluorocytosine to cytotoxic drug 5-fluorouracil. Such therapeutic exosomes administered intranasally, intraperitoneally, or subcutaneously to rats bearing intracerebral glioblastoma cells inhibited their growth. The treatment cured a significant number of animals. Abstract MSC-driven, gene-directed enzyme prodrug therapy (GDEPT) mediated by extracellular vesicles (EV) represents a new paradigm—cell-free GDEPT tumor therapy. In this study, we tested the efficacy of yeast cytosine deaminase::uracilphosphoribosyl transferase (yCD::UPRT-MSC)-exosomes, in the form of conditioned medium (CM) to inhibit the growth of C6 glioblastoma cells both in vitro and in vivo. MSCs isolated from human adipose tissue, umbilical cord, or dental pulp engineered to express the yCD::UPRT gene secreted yCD::UPRT-MSC-exosomes that in the presence of the prodrug 5-fluorocytosine (5-FC), inhibited the growth of rat C6 glioblastoma cells and human primary glioblastoma cells in vitro in a dose-dependent manner. CM from these cells injected repeatedly either intraperitoneally (i.p.) or subcutaneously (s.c.), applied intranasally (i.n.), or infused continuously by an ALZET osmotic pump, inhibited the growth of cerebral C6 glioblastomas in rats. A significant number of rats were cured when CM containing yCD::UPRT-MSC-exosomes conjugated with 5-FC was repeatedly injected i.p. or applied i.n. Cured rats were subsequently resistant to challenges with higher doses of C6 cells. Our data have shown that cell-free GDEPT tumor therapy mediated by the yCD::UPRT-MSC suicide gene EVs for high-grade glioblastomas represents a safer and more practical approach that is worthy of further investigation.
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Affiliation(s)
- Miroslav Tibensky
- Institute of Physiology, Faculty of Medicine, Comenius University, 81372 Bratislava, Slovakia; (M.T.); (B.M.)
- Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, 84505 Bratislava, Slovakia
| | - Jana Jakubechova
- Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, 84505 Bratislava, Slovakia;
- Department of Stem Cell Preparation, St. Elisabeth Cancer Institute, 84505 Bratislava, Slovakia;
| | - Ursula Altanerova
- Department of Stem Cell Preparation, St. Elisabeth Cancer Institute, 84505 Bratislava, Slovakia;
| | - Andrea Pastorakova
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, 81108 Bratislava, Slovakia;
| | - Boris Rychly
- Alpha Medical, Ltd., 82606 Bratislava, Slovakia;
| | - Ladislav Baciak
- Central Laboratories, Slovak University of Technology, 81237 Bratislava, Slovakia;
| | - Boris Mravec
- Institute of Physiology, Faculty of Medicine, Comenius University, 81372 Bratislava, Slovakia; (M.T.); (B.M.)
- Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, 84505 Bratislava, Slovakia
| | - Cestmir Altaner
- Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, 84505 Bratislava, Slovakia;
- Department of Stem Cell Preparation, St. Elisabeth Cancer Institute, 84505 Bratislava, Slovakia;
- Correspondence:
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Vicinanza C, Lombardi E, Da Ros F, Marangon M, Durante C, Mazzucato M, Agostini F. Modified mesenchymal stem cells in cancer therapy: A smart weapon requiring upgrades for wider clinical applications. World J Stem Cells 2022; 14:54-75. [PMID: 35126828 PMCID: PMC8788179 DOI: 10.4252/wjsc.v14.i1.54] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 08/06/2021] [Accepted: 12/23/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem stromal cells (MSC) are characterized by the intriguing capacity to home toward cancer cells after systemic administration. Thus, MSC can be harnessed as targeted delivery vehicles of cytotoxic agents against tumors. In cancer patients, MSC based advanced cellular therapies were shown to be safe but their clinical efficacy was limited. Indeed, the amount of systemically infused MSC actually homing to human cancer masses is insufficient to reduce tumor growth. Moreover, induction of an unequivocal anticancer cytotoxic phenotype in expanded MSC is necessary to achieve significant therapeutic efficacy. Ex vivo cell modifications are, thus, required to improve anti-cancer properties of MSC. MSC based cellular therapy products must be handled in compliance with good manufacturing practice (GMP) guidelines. In the present review we include MSC-improving manipulation approaches that, even though actually tested at preclinical level, could be compatible with GMP guidelines. In particular, we describe possible approaches to improve MSC homing on cancer, including genetic engineering, membrane modification and cytokine priming. Similarly, we discuss appropriate modalities aimed at inducing a marked cytotoxic phenotype in expanded MSC by direct chemotherapeutic drug loading or by genetic methods. In conclusion, we suggest that, to configure MSC as a powerful weapon against cancer, combinations of clinical grade compatible modification protocols that are currently selected, should be introduced in the final product. Highly standardized cancer clinical trials are required to test the efficacy of ameliorated MSC based cell therapies.
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Affiliation(s)
- Carla Vicinanza
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Elisabetta Lombardi
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Francesco Da Ros
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Miriam Marangon
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Cristina Durante
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Mario Mazzucato
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Francesco Agostini
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
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Yassine S, Alaaeddine N. Mesenchymal Stem Cell Exosomes and Cancer: Controversies and Prospects. Adv Biol (Weinh) 2021; 6:e2101050. [PMID: 34939371 DOI: 10.1002/adbi.202101050] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 11/11/2021] [Indexed: 12/13/2022]
Abstract
Mesenchymal stem cells (MSCs) have displayed a novel therapeutic strategy for a wide range of diseases and conditions. Their secretome and exosome-based paracrine activity are considered as the main processes harboring their diverse therapeutic properties. Several investigations have examined the effects of MSC-derived exosomes on cancer growth, yet, controversial results have always emerged. Although MSC-derived exosomes are able to rigorously enforce the repression of cancer proliferation and progression, it is shown that MSCs exosomal activity displays numerous protumorigenic effects. This discrepancy over the dual effects of MSCs on cancer growth may be mediated by many factors including experimental design, stem cells origins, culture conditions, in addition to cancer-MSCs cross-talks. Despite the controversial effects of MSCs on carcinogenesis, scientists are able to overcome a number of obstacles by modifying MSCs to deliver antioncogenic miRNAs, anticancer drugs, and oncolytic viruses into tumor sites. This review discusses the controversial effects of MSC-derived exosomes on tumorigenesis, investigates the main causes that underlie this discrepancy, summarizes the pattern of engineered-MSCs, and finally highlights how future studies should advance the research in the field of MSCs-based cancer therapies in order to accelerate the transition from preclinical studies to clinical practice.
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Affiliation(s)
- Sirine Yassine
- Neuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Beirut, 1100, Lebanon
| | - Nada Alaaeddine
- Neuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Beirut, 1100, Lebanon
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Abstract
The multipotent mesenchymal stem/stromal cells (MSCs), initially discovered from bone marrow in 1976, have been identified in nearly all tissues of human body now. The multipotency of MSCs allows them to give rise to osteocytes, chondrocytes, adipocytes, and other lineages. Moreover, armed with the immunomodulation capacity and tumor-homing property, MSCs are of special relevance for cell-based therapies in the treatment of cancer. However, hampered by lack of knowledge about the controversial roles that MSC plays in the crosstalk with tumors, limited progress has been made with regard to translational medicine. Therefore, in this review, we discuss the prospects of MSC-associated anticancer strategies in light of therapeutic mechanisms and signal transduction pathways. In addition, the clinical trials designed to appraise the efficacy and safety of MSC-based anticancer therapies will be assessed according to published data.
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Affiliation(s)
- Tianxia Lan
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, People's Republic of China
| | - Min Luo
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, People's Republic of China.
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, People's Republic of China.
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Xuan X, Tian C, Zhao M, Sun Y, Huang C. Mesenchymal stem cells in cancer progression and anticancer therapeutic resistance. Cancer Cell Int 2021; 21:595. [PMID: 34736460 PMCID: PMC8570012 DOI: 10.1186/s12935-021-02300-4] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Accepted: 10/26/2021] [Indexed: 12/26/2022] Open
Abstract
Increasing evidence indicates that the tumor microenvironment appears to play an increasingly important role in cancer progression and therapeutic resistance. Several types of cells within the tumor stroma had distinct impacts on cancer progression, either promoting or inhibiting cancer cell growth. Mesenchymal stem cells (MSCs) are a distinct type of cells that is linked to tumor development. MSCs are recognized for homing to tumor locations and promoting or inhibiting cancer cell proliferation, angiogenesis and metastasis. Moreover, emerging studies suggests that MSCs are also involved in therapeutic resistance. In this review, we analyzed the existing researches and elaborate on the functions of MSCs in cancer progression and anticancer therapeutic resistance, demonstrating that MSCs may be a viable cancer therapeutic target.
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Affiliation(s)
- Xiuyun Xuan
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
| | - Chunxia Tian
- Department of Cardiology, Hubei Provincial Hospital of TCM, Wuhan, 430022, Hubei, China
| | - Mengjie Zhao
- Department of Dermatology, Zhongnan Hospital, Wuhan University, Wuhan, 430022, Hubei, China.
| | - Yanhong Sun
- Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.
| | - Changzheng Huang
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China.
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Karimi-Shahri M, Javid H, Sharbaf Mashhad A, Yazdani S, Hashemy SI. Mesenchymal stem cells in cancer therapy; the art of harnessing a foe to a friend. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2021; 24:1307-1323. [PMID: 35096289 PMCID: PMC8769515 DOI: 10.22038/ijbms.2021.58227.12934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 08/04/2021] [Indexed: 12/09/2022]
Abstract
For a long time, mesenchymal stem cells (MSCs) were discussed only as stem cells which could give rise to different types of cells. However, when it became clear that their presence in the tumor microenvironment (TME) was like a green light for tumorigenesis, they emerged from the ashes. This review was arranged to provide a comprehensive and precise description of MSCs' role in regulating tumorigenesis and to discuss the dark and the bright sides of cancer treatment strategies using MSCs. To gather the details about MSCs, we made an intensive literature review using keywords, including MSCs, tumor microenvironment, tumorigenesis, and targeted therapy. Through transferring cytokines, growth factors, and microRNAs, MSCs maintain the cancer stem cell population, increase angiogenesis, provide a facility for cancer metastasis, and shut down the anti-tumor activity of the immune system. Although MSCs progress tumorigenesis, there is a consensus that these cells could be used as a vehicle to transfer anti-cancer agents into the tumor milieu. This feature opened a new chapter in MSCs biology, this time from the therapeutic perspective. Although the data are not sufficient, the advent of new genetic engineering methods might make it possible to engage these cells as Trojan horses to eliminate the malignant population. So many years of investigation showed that MSCs are an important group of cells, residing in the TME, studying the function of which not only could add a delicate series of information to the process of tumorigenesis but also could revolutionize cancer treatment strategies.
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Affiliation(s)
- Mehdi Karimi-Shahri
- Department of Pathology, School of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
- Department of Pathology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Javid
- Department of Medical Laboratory Sciences, Varastegan Institute for Medical Sciences, Mashhad, Iran
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alireza Sharbaf Mashhad
- Department of Medical Laboratory Sciences, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Shaghayegh Yazdani
- Department of Medical Laboratory Sciences, Ilam Institute for Medical Sciences, Ilam, Iran
| | - Seyed Isaac Hashemy
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Horst EN, Bregenzer ME, Mehta P, Snyder CS, Repetto T, Yang-Hartwich Y, Mehta G. Personalized models of heterogeneous 3D epithelial tumor microenvironments: Ovarian cancer as a model. Acta Biomater 2021; 132:401-420. [PMID: 33940195 PMCID: PMC8969826 DOI: 10.1016/j.actbio.2021.04.041] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 04/15/2021] [Accepted: 04/20/2021] [Indexed: 02/07/2023]
Abstract
Intractable human diseases such as cancers, are context dependent, unique to both the individual patient and to the specific tumor microenvironment. However, conventional cancer treatments are often nonspecific, targeting global similarities rather than unique drivers. This limits treatment efficacy across heterogeneous patient populations and even at different tumor locations within the same patient. Ultimately, this poor efficacy can lead to adverse clinical outcomes and the development of treatment-resistant relapse. To prevent this and improve outcomes, it is necessary to be selective when choosing a patient's optimal adjuvant treatment. In this review, we posit the use of personalized, tumor-specific models (TSM) as tools to achieve this remarkable feat. First, using ovarian cancer as a model disease, we outline the heterogeneity and complexity of both the cellular and extracellular components in the tumor microenvironment. Then we examine the advantages and disadvantages of contemporary cancer models and the rationale for personalized TSM. We discuss how to generate precision 3D models through careful and detailed analysis of patient biopsies. Finally, we provide clinically relevant applications of these versatile personalized cancer models to highlight their potential impact. These models are ideal for a myriad of fundamental cancer biology and translational studies. Importantly, these approaches can be extended to other carcinomas, facilitating the discovery of new therapeutics that more effectively target the unique aspects of each individual patient's TME. STATEMENT OF SIGNIFICANCE: In this article, we have presented the case for the application of biomaterials in developing personalized models of complex diseases such as cancers. TSM could bring about breakthroughs in the promise of precision medicine. The critical components of the diverse tumor microenvironments, that lead to treatment failures, include cellular- and extracellular matrix- heterogeneity, and biophysical signals to the cells. Therefore, we have described these dynamic components of the tumor microenvironments, and have highlighted how contemporary biomaterials can be utilized to create personalized in vitro models of cancers. We have also described the application of the TSM to predict the dynamic patterns of disease progression, and predict effective therapies that can produce durable responses, limit relapses, and treat any minimal residual disease.
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Affiliation(s)
- Eric N Horst
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, United States
| | - Michael E Bregenzer
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, United States
| | - Pooja Mehta
- Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, United States
| | - Catherine S Snyder
- Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, United States
| | - Taylor Repetto
- Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, United States
| | - Yang Yang-Hartwich
- Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, Yale University, New Haven, CT 06510, United States
| | - Geeta Mehta
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, United States; Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, United States; Macromolecular Science and Engineering, University of Michigan, Ann Arbor, MI 48109, United States; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, United States; Precision Health, University of Michigan, Ann Arbor, MI 48109, United States.
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Rat Adipose-Derived Stromal Cells (ADSCs) Increases the Glioblastoma Growth and Decreases the Animal Survival. Stem Cell Rev Rep 2021; 18:1495-1509. [PMID: 34403074 DOI: 10.1007/s12015-021-10227-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/25/2021] [Indexed: 12/22/2022]
Abstract
Many studies have shown that mesenchymal stromal cells (MSCs) and their secreted factors may modulate the biology of tumor cells. However, how these interactions happen in vivo remains unclear. In the present study, we investigated the effects of rat adipose-derived stromal cells (ADSCs) and their conditioned medium (ADSC-CM) in glioma tumor growth and malignancy in vivo. Our results showed that when we co-injected C6 cells plus ADSCs into the rat brains, the tumors generated were larger and the animals exhibited shorter survival, when compared with tumors of the animals that received only C6 cells or C6 cells pre-treated with ADSC-CM. We further showed that the animals that received C6 plus ADSC did not present enhanced expression of CD73 (a gene highly expressed in ADSCs), indicating that the tumor volume observed in these animals was not a mere consequence of the higher density of cells administered in this group. Finally, we showed that the animals that received C6 + ADSC presented tumors with larger necrosis areas and greater infiltration of immune cells. These results indicate that the immunoregulatory properties of ADSCs and its contribution to tumor stroma can support tumor growth leading to larger zones of necrosis, recruitment of immune cells, thus facilitating tumor progression. Our data provide new insights into the way by which ADSCs and tumor cells interact and highlight the importance of understanding the fate and roles of MSCs in tumor sites in vivo, as well as their intricate crosstalk with cancer cells.
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30
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Yadav P, Jain J, Sherje AP. Recent advances in nanocarriers-based drug delivery for cancer therapeutics: A review. REACT FUNCT POLYM 2021. [DOI: 10.1016/j.reactfunctpolym.2021.104970] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Ding Y, Wang C, Sun Z, Wu Y, You W, Mao Z, Wang W. Mesenchymal Stem Cells Engineered by Nonviral Vectors: A Powerful Tool in Cancer Gene Therapy. Pharmaceutics 2021; 13:pharmaceutics13060913. [PMID: 34205513 PMCID: PMC8235299 DOI: 10.3390/pharmaceutics13060913] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 06/09/2021] [Accepted: 06/16/2021] [Indexed: 12/14/2022] Open
Abstract
Due to their "tumor homing" and "immune privilege" characteristics, the use of mesenchymal stem cells (MSCs) has been proposed as a novel tool against cancer. MSCs are genetically engineered in vitro and then utilized to deliver tumoricidal agents, including prodrugs and bioactive molecules, to tumors. The genetic modification of MSCs can be achieved by various vectors, and in most cases viral vectors are used; however, viruses may be associated with carcinogenesis and immunogenicity, restricting their clinical translational potential. As such, nonviral vectors have emerged as a potential solution to address these limitations and have gradually attracted increasing attention. In this review, we briefly revisit the current knowledge about MSC-based cancer gene therapy. Then, we summarize the advantages and challenges of nonviral vectors for MSC transfection. Finally, we discuss recent advances in the development of new nonviral vectors, which have provided promising strategies to overcome obstacles in the gene modulation of MSCs.
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Affiliation(s)
- Yuan Ding
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China; (Y.D.); (C.W.); (Z.S.); (Y.W.); (W.Y.)
- Key Laboratory, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou 310009, China
- Research Center, Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou 310009, China
- Clinical Medicine Innovation Center, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease, Zhejiang University, Hangzhou 310009, China
- Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou 310009, China
- Cancer Center, Zhejiang University, Hangzhou 310009, China
| | - Chenyang Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China; (Y.D.); (C.W.); (Z.S.); (Y.W.); (W.Y.)
- Key Laboratory, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou 310009, China
- Research Center, Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou 310009, China
- Clinical Medicine Innovation Center, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease, Zhejiang University, Hangzhou 310009, China
- Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou 310009, China
- Cancer Center, Zhejiang University, Hangzhou 310009, China
| | - Zhongquan Sun
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China; (Y.D.); (C.W.); (Z.S.); (Y.W.); (W.Y.)
- Key Laboratory, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou 310009, China
- Research Center, Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou 310009, China
- Clinical Medicine Innovation Center, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease, Zhejiang University, Hangzhou 310009, China
- Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou 310009, China
- Cancer Center, Zhejiang University, Hangzhou 310009, China
| | - Yingsheng Wu
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China; (Y.D.); (C.W.); (Z.S.); (Y.W.); (W.Y.)
- Key Laboratory, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou 310009, China
- Research Center, Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou 310009, China
- Clinical Medicine Innovation Center, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease, Zhejiang University, Hangzhou 310009, China
- Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou 310009, China
- Cancer Center, Zhejiang University, Hangzhou 310009, China
| | - Wanlu You
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China; (Y.D.); (C.W.); (Z.S.); (Y.W.); (W.Y.)
- Key Laboratory, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou 310009, China
- Research Center, Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou 310009, China
- Clinical Medicine Innovation Center, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease, Zhejiang University, Hangzhou 310009, China
- Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou 310009, China
- Cancer Center, Zhejiang University, Hangzhou 310009, China
| | - Zhengwei Mao
- Key Laboratory, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou 310009, China
- MOE Key Laboratory, Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, China
- Correspondence: (Z.M.); (W.W.); Tel.: +86-15168215834 (Z.M.); +86-0571-87783820 (W.W.)
| | - Weilin Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China; (Y.D.); (C.W.); (Z.S.); (Y.W.); (W.Y.)
- Key Laboratory, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou 310009, China
- Research Center, Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou 310009, China
- Clinical Medicine Innovation Center, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease, Zhejiang University, Hangzhou 310009, China
- Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou 310009, China
- Cancer Center, Zhejiang University, Hangzhou 310009, China
- Correspondence: (Z.M.); (W.W.); Tel.: +86-15168215834 (Z.M.); +86-0571-87783820 (W.W.)
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Eiro N, Fraile M, Fernández-Francos S, Sánchez R, Costa LA, Vizoso FJ. Importance of the origin of mesenchymal (stem) stromal cells in cancer biology: "alliance" or "war" in intercellular signals. Cell Biosci 2021; 11:109. [PMID: 34112253 PMCID: PMC8194017 DOI: 10.1186/s13578-021-00620-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 05/31/2021] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stem cells (MSCs) play a central role in the intercellular signaling within the tumor microenvironment (TME), exchanging signals with cancer cells and tumor stromal cells, such as cancer-associated fibroblasts and inflammatory mononuclear cells. Research attributes both pro-tumor and anti-tumor actions to MSCs; however, evidence indicates that MSCs specific effect on the tumor depends on the source of the MSCs and the type of tumor. There are consistent data proving that MSCs from reproductive tissues, such as the uterus, umbilical cord or placenta, have potent anti-tumor effects and tropism towards tumor tissues. More interestingly, products derived from MSCs, such as secretome or extracellular vesicles, seem to reproduce the effects of their parental cells, showing a potential advantage for clinical treatments by avoiding the drawbacks associated with cell therapy. Given these perspectives, it appears necessary new research to optimize the production, safety and antitumor potency of the products derived from the MSCs suitable for oncological therapies.
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Affiliation(s)
- Noemi Eiro
- Unit Research, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33290, Gijón, Asturias, Spain.
| | - Maria Fraile
- Unit Research, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33290, Gijón, Asturias, Spain
| | - Silvia Fernández-Francos
- Unit Research, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33290, Gijón, Asturias, Spain
| | - Rosario Sánchez
- Department of Surgery, Fundación Hospital de Jove, 33290, Gijón, Asturias, Spain
| | - Luis A Costa
- Unit Research, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33290, Gijón, Asturias, Spain
| | - Francisco J Vizoso
- Unit Research, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33290, Gijón, Asturias, Spain. .,Department of Surgery, Fundación Hospital de Jove, 33290, Gijón, Asturias, Spain.
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Ivolgin DA, Kudlay DA. Mesenchymal multipotent stromal cells and cancer safety: two sides of the same coin or a double-edged sword (review of foreign literature). RUSSIAN JOURNAL OF PEDIATRIC HEMATOLOGY AND ONCOLOGY 2021; 8:64-84. [DOI: 10.21682/2311-1267-2021-8-1-64-84] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
Knowledge about the mechanisms of action of mesenchymal multipotent stromal cells (MSC) has undergone a significant evolution since their discovery. From the first attempts to use the remarkable properties of MSC in restoring the functions of organs and tissues, the most important question arose – how safe their use would be? One of the aspects of safety of the use of such biomaterial is tumorogenicity and oncogenicity. Numerous studies have shown that the mechanisms by which MSC realize their regenerative potential can, in principle, have a stimulating effect on tumor cells. This review presents specific mechanisms that have a potentially pro-tumor effect, which include the homing of MSC to the tumor site, support for replicative and proliferative signaling of both cancer cells and cancer stem cells, angiogenesis, and effects on the epithelial-mesenchymal transition. Along with pro-tumor mechanisms, the mechanisms of possible antitumor action are also described – direct suppression of tumor growth, loading and transportation of chemotherapeutic agents, oncolytic viruses, genetic modifications for targeting cancer, delivery of “suicide genes” to the tumor. Also, in conclusion, a small review of the current clinical trials of MSC as antitumor agents for malignant neoplasms of various localization (gastrointestinal tract, lungs, ovaries) is given.
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Affiliation(s)
- D. A. Ivolgin
- I.I. Mechnikov North-Western State Medical University, Ministry of Health of Russia
| | - D. A. Kudlay
- JSC “GENERIUM”;
I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia (Sechenov University);
National Research Center – Institute of Immunology Federal Medical-Biological Agency of Russia
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Fernández-Francos S, Eiro N, Costa LA, Escudero-Cernuda S, Fernández-Sánchez ML, Vizoso FJ. Mesenchymal Stem Cells as a Cornerstone in a Galaxy of Intercellular Signals: Basis for a New Era of Medicine. Int J Mol Sci 2021; 22:ijms22073576. [PMID: 33808241 PMCID: PMC8036553 DOI: 10.3390/ijms22073576] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 03/25/2021] [Accepted: 03/26/2021] [Indexed: 02/06/2023] Open
Abstract
Around 40% of the population will suffer at some point in their life a disease involving tissue loss or an inflammatory or autoimmune process that cannot be satisfactorily controlled with current therapies. An alternative for these processes is represented by stem cells and, especially, mesenchymal stem cells (MSC). Numerous preclinical studies have shown MSC to have therapeutic effects in different clinical conditions, probably due to their mesodermal origin. Thereby, MSC appear to play a central role in the control of a galaxy of intercellular signals of anti-inflammatory, regenerative, angiogenic, anti-fibrotic, anti-oxidative stress effects of anti-apoptotic, anti-tumor, or anti-microbial type. This concept forces us to return to the origin of natural physiological processes as a starting point to understand the evolution of MSC therapy in the field of regenerative medicine. These biological effects, demonstrated in countless preclinical studies, justify their first clinical applications, and draw a horizon of new therapeutic strategies. However, several limitations of MSC as cell therapy are recognized, such as safety issues, handling difficulties for therapeutic purposes, and high economic cost. For these reasons, there is an ongoing tendency to consider the use of MSC-derived secretome products as a therapeutic tool, since they reproduce the effects of their parent cells. However, it will be necessary to resolve key aspects, such as the choice of the ideal type of MSC according to their origin for each therapeutic indication and the implementation of new standardized production strategies. Therefore, stem cell science based on an intelligently designed production of MSC and or their derivative products will be able to advance towards an innovative and more personalized medical biotechnology.
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Affiliation(s)
| | - Noemi Eiro
- Research Unit, Fundación Hospital de Jove, 33290 Gijón, Spain; (S.F.-F.); (L.A.C.)
- Correspondence: (N.E.); (F.J.V.); Tel.: +34-985320050 (ext. 84216)
| | - Luis A. Costa
- Research Unit, Fundación Hospital de Jove, 33290 Gijón, Spain; (S.F.-F.); (L.A.C.)
| | - Sara Escudero-Cernuda
- Department of Physical and Analytical Chemistry, Faculty of Chemistry, University of Oviedo, 33006 Oviedo, Spain; (S.E.-C.); (M.L.F.-S.)
| | - María Luisa Fernández-Sánchez
- Department of Physical and Analytical Chemistry, Faculty of Chemistry, University of Oviedo, 33006 Oviedo, Spain; (S.E.-C.); (M.L.F.-S.)
| | - Francisco J. Vizoso
- Research Unit, Fundación Hospital de Jove, 33290 Gijón, Spain; (S.F.-F.); (L.A.C.)
- Correspondence: (N.E.); (F.J.V.); Tel.: +34-985320050 (ext. 84216)
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Engineered microtissues for the bystander therapy against cancer. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2021; 121:111854. [PMID: 33579487 DOI: 10.1016/j.msec.2020.111854] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 12/24/2020] [Accepted: 12/28/2020] [Indexed: 12/28/2022]
Abstract
Thymidine kinase expressing human adipose mesenchymal stem cells (TK-hAMSCs) in combination with ganciclovir (GCV) are an effective platform for antitumor bystander therapy in mice models. However, this strategy requires multiple TK-hAMSCs administrations and a substantial number of cells. Therefore, for clinical translation, it is necessary to find a biocompatible scaffold providing TK-hAMSCs retention in the implantation site against their rapid wash-out. We have developed a microtissue (MT) composed by TKhAMSCs and a scaffold made of polylactic acid microparticles and cell-derived extracellular matrix deposited by hAMSCs. The efficacy of these MTs as vehicles for TK-hAMSCs/GCV bystander therapy was evaluated in a rodent model of human prostate cancer. Subcutaneously implanted MTs were integrated in the surrounding tissue, allowing neovascularization and maintenance of TK-hAMSCs viability. Furthermore, MTs implanted beside tumors allowed TK-hAMSCs migration towards tumor cells and, after GCV administration, inhibited tumor growth. These results indicate that TK-hAMSCs-MTs are promising cell reservoirs for clinical use of therapeutic MSCs in bystander therapies.
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Jafari A, Rezaei-Tavirani M, Farhadihosseinabadi B, Zali H, Niknejad H. Human amniotic mesenchymal stem cells to promote/suppress cancer: two sides of the same coin. Stem Cell Res Ther 2021; 12:126. [PMID: 33579346 PMCID: PMC7881457 DOI: 10.1186/s13287-021-02196-x] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 01/27/2021] [Indexed: 02/08/2023] Open
Abstract
Cancer is a leading cause of death in both developed and developing countries, and because of population growth and aging, it is a growing medical burden worldwide. With robust development in medicine, the use of stem cells has opened new treatment modalities in cancer therapy. In adult stem cells, mesenchymal stem cells (MSCs) are showing rising promise in cancer treatment due to their unique properties. Among different sources of MSCs, human amniotic fluid/membrane is an attractive and suitable reservoir. There are conflicting opinions about the role of human amniotic membrane/fluid mesenchymal stem cells (hAMSCS/hAFMSCs) in cancer, as some studies demonstrating the anticancer effects of these cells and others suggesting their progressive effects on cancer. This review focuses on recent findings about the role of hAMSCs/hAFMSCs in cancer treatment and summarizes the suppressing as well as promoting effects of these cells on cancer progression and underling mechanisms.
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Affiliation(s)
- Ameneh Jafari
- Department of Basic Sciences, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mostafa Rezaei-Tavirani
- Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Hakimeh Zali
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hassan Niknejad
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Liang W, Chen X, Zhang S, Fang J, Chen M, Xu Y, Chen X. Mesenchymal stem cells as a double-edged sword in tumor growth: focusing on MSC-derived cytokines. Cell Mol Biol Lett 2021; 26:3. [PMID: 33472580 PMCID: PMC7818947 DOI: 10.1186/s11658-020-00246-5] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 12/27/2020] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stem cells (MSCs) show homing capacity towards tumor sites. Numerous reports indicate that they are involved in multiple tumor-promoting processes through several mechanisms, including immunosuppression; stimulation of angiogenesis; transition to cancer-associated fibroblasts; inhibition of cancer cell apoptosis; induction of epithelial-mesenchymal transition (EMT); and increase metastasis and chemoresistance. However, other studies have shown that MSCs suppress tumor growth by suppressing angiogenesis, incrementing inflammatory infiltration, apoptosis and cell cycle arrest, and inhibiting the AKT and Wnt signaling pathways. In this review, we discuss the supportive and suppressive impacts of MSCs on tumor progression and metastasis. We also discuss MSC-based therapeutic strategies for cancer based on their potential for homing to tumor sites.
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Affiliation(s)
- Wenqing Liang
- Department of Orthopaedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, 355 Xinqiao Road, Dinghai District, Zhoushan, 316000, Zhejiang, People's Republic of China.
| | - Xiaozhen Chen
- College of Medicine, Shaoxing University, Shaoxing, 312000, Zhejiang, People's Republic of China
| | - Songou Zhang
- College of Medicine, Shaoxing University, Shaoxing, 312000, Zhejiang, People's Republic of China
| | - Jian Fang
- College of Medicine, Shaoxing University, Shaoxing, 312000, Zhejiang, People's Republic of China
| | - Meikai Chen
- Department of Orthopaedics, Shaoxing People's Hospital, The First Affiliated Hospital of Shaoxing University, Shaoxing, 312000, Zhejiang, People's Republic of China
| | - Yifan Xu
- Department of Orthopaedics, Shaoxing People's Hospital, The First Affiliated Hospital of Shaoxing University, Shaoxing, 312000, Zhejiang, People's Republic of China
| | - Xuerong Chen
- Department of Orthopaedics, Shaoxing People's Hospital, The First Affiliated Hospital of Shaoxing University, Shaoxing, 312000, Zhejiang, People's Republic of China
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Tarar A, Alyami EM, Peng CA. Mesenchymal stem cells anchored with thymidine phosphorylase for doxifluridine-mediated cancer therapy. RSC Adv 2021; 11:1394-1403. [PMID: 35424143 PMCID: PMC8693507 DOI: 10.1039/d0ra10263f] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Accepted: 12/23/2020] [Indexed: 12/11/2022] Open
Abstract
Many tumors express thymidine phosphorylase (TYMP) with various levels, however due to tumor heterogeneity, the amount of TYMP is usually not enough to convert prodrug doxifluridine (5'-DFUR) to toxic drug 5-fluorouracil (5-FU). Since human mesenchymal stem cells (hMSCs) have unique features of tumor-tropism and low immunogenicity, the purpose of this study is to use mesenchymal stem cells as carriers to deliver TYMP to cancer cells and then trigger their death by administrating doxifluridine. First, the TYMP gene sequence and core streptavidin (core SA) were constructed into pET-30a(+) plasmid. After bacterial transformation and colony screening, TYMP-SA fusion protein was expressed by IPTG induction and purified by immobilized metal affinity chromatography and characterized by SDS-PAGE and western blot with a clear band at 75 kDa. The characterized TYMP-SA was further anchored on the cell membrane of biotinylated hMSCs via biotin-streptavidin binding. hMSCs anchored with TYMP-SA were then co-cultured with adenocarcinoma A549 cells (with different ratios) and treated with 100 μM prodrug doxifluridine over the course of four days. Our results showed that a 2 : 1 ratio led to the eradication of A549 cells at the end of the experiment with less than 5% confluency, in comparison with the 1 : 1 and 1 : 2 ratios which still had about 13% and 20% confluency respectively. In conclusion, harnessing hMSCs as cell carriers for the delivery of TYMP enzyme to cancer cells could lead to significant cell death post-treatment of the prodrug doxifluridine.
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Affiliation(s)
- Ammar Tarar
- Department of Chemical & Biological Engineering, University of Idaho Engineering Physics Building 421, 875 Perimeter Drive Moscow ID 83844-0904 USA +1-208-885-7461
| | - Esmael M Alyami
- Department of Chemical & Biological Engineering, University of Idaho Engineering Physics Building 421, 875 Perimeter Drive Moscow ID 83844-0904 USA +1-208-885-7461
| | - Ching-An Peng
- Department of Chemical & Biological Engineering, University of Idaho Engineering Physics Building 421, 875 Perimeter Drive Moscow ID 83844-0904 USA +1-208-885-7461
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Pawitan JA, Bui TA, Mubarok W, Antarianto RD, Nurhayati RW, Dilogo IH, Oceandy D. Enhancement of the Therapeutic Capacity of Mesenchymal Stem Cells by Genetic Modification: A Systematic Review. Front Cell Dev Biol 2020; 8:587776. [PMID: 33195245 PMCID: PMC7661472 DOI: 10.3389/fcell.2020.587776] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 10/01/2020] [Indexed: 12/13/2022] Open
Abstract
Background The therapeutic capacity of mesenchymal stem cells (also known as mesenchymal stromal cells/MSCs) depends on their ability to respond to the need of the damaged tissue by secreting beneficial paracrine factors. MSCs can be genetically engineered to express certain beneficial factors. The aim of this systematic review is to compile and analyze published scientific literatures that report the use of engineered MSCs for the treatment of various diseases/conditions, to discuss the mechanisms of action, and to assess the efficacy of engineered MSC treatment. Methods We retrieved all published studies in PubMed/MEDLINE and Cochrane Library on July 27, 2019, without time restriction using the following keywords: “engineered MSC” and “therapy” or “manipulated MSC” and “therapy.” In addition, relevant articles that were found during full text search were added. We identified 85 articles that were reviewed in this paper. Results Of the 85 articles reviewed, 51 studies reported the use of engineered MSCs to treat tumor/cancer/malignancy/metastasis, whereas the other 34 studies tested engineered MSCs in treating non-tumor conditions. Most of the studies reported the use of MSCs in animal models, with only one study reporting a trial in human subjects. Thirty nine studies showed that the expression of beneficial paracrine factors would significantly enhance the therapeutic effects of the MSCs, whereas thirty three studies showed moderate effects, and one study in humans reported no effect. The mechanisms of action for MSC-based cancer treatment include the expression of “suicide genes,” induction of tumor cell apoptosis, and delivery of cytokines to induce an immune response against cancer cells. In the context of the treatment of non-cancerous diseases, the mechanism described in the reviewed papers included the expression of angiogenic, osteogenic, and growth factors. Conclusion The therapeutic capacity of MSCs can be enhanced by inducing the expression of certain paracrine factors by genetic modification. Genetically engineered MSCs have been used successfully in various animal models of diseases. However, the results should be interpreted cautiously because animal models might not perfectly represent real human diseases. Therefore, further studies are needed to explore the translational potential of genetically engineered MSCs.
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Affiliation(s)
- Jeanne Adiwinata Pawitan
- Department of Histology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.,Stem Cell Medical Technology Integrated Service Unit, Dr. Cipto Mangunkusumo General Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.,Stem Cell and Tissue Engineering Research Center, Indonesia Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Thuy Anh Bui
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, United Kingdom
| | - Wildan Mubarok
- Division of Chemical Engineering, Department of Materials Engineering Science, Graduate School of Engineering Science, Osaka University, Toyonaka, Japan
| | - Radiana Dhewayani Antarianto
- Department of Histology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.,Stem Cell and Tissue Engineering Research Center, Indonesia Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Retno Wahyu Nurhayati
- Stem Cell and Tissue Engineering Research Center, Indonesia Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.,Department of Biochemistry and Molecular Biology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Ismail Hadisoebroto Dilogo
- Stem Cell Medical Technology Integrated Service Unit, Dr. Cipto Mangunkusumo General Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.,Stem Cell and Tissue Engineering Research Center, Indonesia Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.,Department of Orthopaedic and Traumatology, Dr. Cipto Mangunkusumo General Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Delvac Oceandy
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, United Kingdom.,Department of Biomedical Science, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
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Golinelli G, Mastrolia I, Aramini B, Masciale V, Pinelli M, Pacchioni L, Casari G, Dall'Ora M, Soares MBP, Damasceno PKF, Silva DN, Dominici M, Grisendi G. Arming Mesenchymal Stromal/Stem Cells Against Cancer: Has the Time Come? Front Pharmacol 2020; 11:529921. [PMID: 33117154 PMCID: PMC7553050 DOI: 10.3389/fphar.2020.529921] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Accepted: 09/08/2020] [Indexed: 12/11/2022] Open
Abstract
Since mesenchymal stromal/stem cells (MSCs) were discovered, researchers have been drawn to study their peculiar biological features, including their immune privileged status and their capacity to selectively migrate into inflammatory areas, including tumors. These properties make MSCs promising cellular vehicles for the delivery of therapeutic molecules in the clinical setting. In recent decades, the engineering of MSCs into biological vehicles carrying anticancer compounds has been achieved in different ways, including the loading of MSCs with chemotherapeutics or drug functionalized nanoparticles (NPs), genetic modifications to force the production of anticancer proteins, and the use of oncolytic viruses. Recently, it has been demonstrated that wild-type and engineered MSCs can release extracellular vesicles (EVs) that contain therapeutic agents. Despite the enthusiasm for MSCs as cyto-pharmaceutical agents, many challenges, including controlling the fate of MSCs after administration, must still be considered. Preclinical results demonstrated that MSCs accumulate in lung, liver, and spleen, which could prevent their engraftment into tumor sites. For this reason, physical, physiological, and biological methods have been implemented to increase MSC concentration in the target tumors. Currently, there are more than 900 registered clinical trials using MSCs. Only a small fraction of these are investigating MSC-based therapies for cancer, but the number of these clinical trials is expected to increase as technology and our understanding of MSCs improve. This review will summarize MSC-based antitumor therapies to generate an increasing awareness of their potential and limits to accelerate their clinical translation.
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Affiliation(s)
- Giulia Golinelli
- Laboratory of Cellular Therapy, Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy
| | - Ilenia Mastrolia
- Laboratory of Cellular Therapy, Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy
| | - Beatrice Aramini
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy
| | - Valentina Masciale
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy
| | - Massimo Pinelli
- Division of Plastic Surgery, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy
| | - Lucrezia Pacchioni
- Division of Plastic Surgery, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy
| | - Giulia Casari
- Laboratory of Cellular Therapy, Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy
| | - Massimiliano Dall'Ora
- Laboratory of Cellular Therapy, Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy
| | - Milena Botelho Pereira Soares
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Brazil.,Health Institute of Technology, SENAI-CIMATEC, Salvador, Brazil
| | - Patrícia Kauanna Fonseca Damasceno
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Brazil.,Health Institute of Technology, SENAI-CIMATEC, Salvador, Brazil
| | - Daniela Nascimento Silva
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Brazil.,Health Institute of Technology, SENAI-CIMATEC, Salvador, Brazil
| | - Massimo Dominici
- Laboratory of Cellular Therapy, Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy.,Rigenerand srl, Modena, Italy
| | - Giulia Grisendi
- Laboratory of Cellular Therapy, Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy.,Rigenerand srl, Modena, Italy
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Wilhelm C, Scherzad A, Bregenzer M, Meyer T, Gehrke T, Kleinsasser N, Hagen R, Hackenberg S. Interaction of head and neck squamous cell carcinoma cells and mesenchymal stem cells under hypoxia and normoxia. Oncol Lett 2020; 20:229. [PMID: 32968451 DOI: 10.3892/ol.2020.12092] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Accepted: 07/23/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) exhibit strong tropism towards tumor tissue. While MSCs generally surround tumors, they can also infiltrate tumors and thereby influence their proliferation. Interactions between MSCs and tumor cells are usually tested under normoxia, but the majority of solid tumors, including head and neck squamous cell carcinoma (HNSCC), are also characterized by hypoxic areas. Hence, the present study aimed to assess the interaction between MSCs and tumor cells under hypoxic conditions. MSCs were cultivated under normoxia and hypoxia, and conditioned media were used to cultivate the HNSCC cell line FaDu. The cell cycle distribution and viability of MSCs and the proliferation of FaDu cells were analyzed under normoxia and hypoxia, and changes in cytokine levels in the conditioned media were evaluated. No cell cycle changes were observed for MSCs after 24 h of cultivation under hypoxia, but the cell viability had declined. Hypoxia also led to a decrease in the proliferation of FaDu cells; however, FaDu cells proliferated faster after 48 h under hypoxia compared with normoxic conditions. This effect was reversed after incubation under normoxia for 72 h and hypoxia for 72 h. While these changes constituted a trend, these differences were not statistically significant. A cytokine assay showed an increase in interleukin (IL)-6 in the hypoxic medium. Overall, the results indicated that there was an interaction between MSCs and tumor cells. The presence or absence of oxygen seemed to influence the functionality of MSCs and their protumorigenic properties, in which IL-6 was identified as a potential mediator. Since MSCs are a component of the tumor stroma, further in vitro and in vivo studies are needed to investigate this interaction in order to develop novel approaches for tumor therapy.
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Affiliation(s)
- Christian Wilhelm
- Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, Julius Maximilian University of Wuerzburg, D-97080 Wuerzburg, Germany
| | - Agmal Scherzad
- Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, Julius Maximilian University of Wuerzburg, D-97080 Wuerzburg, Germany
| | - Maximilian Bregenzer
- Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, Julius Maximilian University of Wuerzburg, D-97080 Wuerzburg, Germany
| | - Till Meyer
- Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, Julius Maximilian University of Wuerzburg, D-97080 Wuerzburg, Germany
| | - Thomas Gehrke
- Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, Julius Maximilian University of Wuerzburg, D-97080 Wuerzburg, Germany
| | - Norbert Kleinsasser
- Department of Otorhinolaryngology, Head and Neck Surgery, Kepler University, A-4020 Linz, Austria
| | - Rudolf Hagen
- Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, Julius Maximilian University of Wuerzburg, D-97080 Wuerzburg, Germany
| | - Stephan Hackenberg
- Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, Julius Maximilian University of Wuerzburg, D-97080 Wuerzburg, Germany
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Tu GXE, Ho YK, Ng ZX, Teo KJ, Yeo TT, Too HP. A facile and scalable in production non-viral gene engineered mesenchymal stem cells for effective suppression of temozolomide-resistant (TMZR) glioblastoma growth. Stem Cell Res Ther 2020; 11:391. [PMID: 32917269 PMCID: PMC7488524 DOI: 10.1186/s13287-020-01899-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 07/28/2020] [Accepted: 08/24/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) serve as an attractive vehicle for cell-directed enzyme prodrug therapy (CDEPT) due to their unique tumour-nesting ability. Such approach holds high therapeutic potential for treating solid tumours including glioblastoma multiforme (GBM), a devastating disease with limited effective treatment options. Currently, it is a common practice in research and clinical manufacturing to use viruses to deliver therapeutic genes into MSCs. However, this is limited by the inherent issues of safety, high cost and demanding manufacturing processes. The aim of this study is to identify a facile, scalable in production and highly efficient non-viral method to transiently engineer MSCs for prolonged and exceptionally high expression of a fused transgene: yeast cytosine deaminase::uracil phosphoribosyl-transferase::green fluorescent protein (CD::UPRT::GFP). METHODS MSCs were transfected with linear polyethylenimine using a cpg-free plasmid encoding the transgene in the presence of a combination of fusogenic lipids and β tubulin deacetylase inhibitor (Enhancer). Process scalability was evaluated in various planar vessels and microcarrier-based bioreactor. The transfection efficiency was determined with flow cytometry, and the therapeutic efficacy of CD::UPRT::GFP expressing MSCs was evaluated in cocultures with temozolomide (TMZ)-sensitive or TMZ-resistant human glioblastoma cell lines. In the presence of 5-fluorocytosine (5FC), the 5-fluorouracil-mediated cytotoxicity was determined by performing colometric MTS assay. In vivo antitumor effects were examined by local injection into subcutaneous TMZ-resistant tumors implanted in the athymic nude mice. RESULTS At > 90% transfection efficiency, the phenotype, differentiation potential and tumour tropism of MSCs were unaltered. High reproducibility was observed in all scales of transfection. The therapeutically modified MSCs displayed strong cytotoxicity towards both TMZ-sensitive and TMZ-resistant U251-MG and U87-MG cell lines only in the presence of 5FC. The effectiveness of this approach was further validated with other well-characterized and clinically annotated patient-derived GBM cells. Additionally, a long-term suppression (> 30 days) of the growth of a subcutaneous TMZ-resistant U-251MG tumour was demonstrated. CONCLUSIONS Collectively, this highly efficient non-viral workflow could potentially enable the scalable translation of therapeutically engineered MSC for the treatment of TMZ-resistant GBM and other applications beyond the scope of this study.
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Affiliation(s)
- Geraldine Xue En Tu
- Department of Biochemistry, National University of Singapore, Singapore, 117596, Singapore
| | - Yoon Khei Ho
- Department of Biochemistry, National University of Singapore, Singapore, 117596, Singapore.
| | - Zhi Xu Ng
- Division of Neurosurgery, Department of General Surgery, Khoo Teck Puat Hospital, Singapore, 768828, Singapore
| | - Ke Jia Teo
- Division of Neurosurgery, Department of General Surgery, National University Hospital, National University Health Systems, Singapore, Singapore
| | - Tseng Tsai Yeo
- Division of Neurosurgery, Department of General Surgery, National University Hospital, National University Health Systems, Singapore, Singapore
| | - Heng-Phon Too
- Department of Biochemistry, National University of Singapore, Singapore, 117596, Singapore
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Gharbavi M, Sharafi A, Ghanbarzadeh S. Mesenchymal Stem Cells: A New Generation of Therapeutic Agents as Vehicles in Gene Therapy. Curr Gene Ther 2020; 20:269-284. [PMID: 32515309 DOI: 10.2174/1566523220666200607190339] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 05/15/2020] [Accepted: 05/19/2020] [Indexed: 12/26/2022]
Abstract
In recent years, mesenchymal stem cells (MSCs) as a new tool for therapeutic gene delivery in clinics have attracted much attention. Their advantages cover longer lifespan, better isolation, and higher transfection efficiency and proliferation rate. MSCs are the preferred approach for cell-based therapies because of their in vitro self-renewal capacity, migrating especially to tumor tissues, as well as anti-inflammatory and immunomodulatory properties. Therefore, they have considerable efficiency in genetic engineering for future clinical applications in cancer gene therapy and other diseases. For improving therapeutic efficiency, targeted therapy of cancers can be achieved through the sustained release of therapeutic agents and functional gene expression induction to the intended tissues. The development of a new vector in gene therapy can improve the durability of a transgene expression. Also, the safety of the vector, if administered systemically, may resolve several problems, such as durability of expression and the host immune response. Currently, MSCs are prominent candidates as cell vehicles for both preclinical and clinical trials due to the secretion of therapeutic agents in several cancers. In the present study, we discuss the status of gene therapy in both viral and non-viral vectors along with their limitations. Throughout this study, the use of several nano-carriers for gene therapy is also investigated. Finally, we critically discuss the promising advantages of MSCs in targeted gene delivery, tumor inhibition and their utilization as the gene carriers in clinical situations.
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Affiliation(s)
- Mahmoud Gharbavi
- Department of Pharmaceutical Biomaterials, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan,
Iran,Cancer Gene Therapy Research Center, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan,
Iran,Zanjan Applied Pharmacology Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Ali Sharafi
- Zanjan Applied Pharmacology Research Center, Zanjan University of Medical Sciences, Zanjan, Iran,Zanjan Pharmaceutical Biotechnology Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Saeed Ghanbarzadeh
- Cancer Gene Therapy Research Center, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan,
Iran,Zanjan Pharmaceutical Nanotechnology Research Center and Department of Pharmaceutics, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran
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44
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Munteanu R, Onaciu A, Moldovan C, Zimta AA, Gulei D, Paradiso AV, Lazar V, Berindan-Neagoe I. Adipocyte-Based Cell Therapy in Oncology: The Role of Cancer-Associated Adipocytes and Their Reinterpretation as Delivery Platforms. Pharmaceutics 2020; 12:E402. [PMID: 32354024 PMCID: PMC7284545 DOI: 10.3390/pharmaceutics12050402] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 04/22/2020] [Accepted: 04/23/2020] [Indexed: 12/24/2022] Open
Abstract
Cancer-associated adipocytes have functional roles in tumor development through secreted adipocyte-derived factors and exosomes and also through metabolic symbiosis, where the malignant cells take up the lactate, fatty acids and glutamine produced by the neighboring adipocytes. Recent research has demonstrated the value of adipocytes as cell-based delivery platforms for drugs (or prodrugs), nucleic acids or loaded nanoparticles for cancer therapy. This strategy takes advantage of the biocompatibility of the delivery system, its ability to locate the tumor site and also the predisposition of cancer cells to come in functional contact with the adipocytes from the tumor microenvironment for metabolic sustenance. Also, their exosomal content can be used in the context of cancer stem cell reprogramming or as a delivery vehicle for different cargos, like non-coding nucleic acids. Moreover, the process of adipocytes isolation, processing and charging is quite straightforward, with minimal economical expenses. The present review comprehensively presents the role of adipocytes in cancer (in the context of obese and non-obese individuals), the main methods for isolation and characterization and also the current therapeutic applications of these cells as delivery platforms in the oncology sector.
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Affiliation(s)
- Raluca Munteanu
- Research Center for Advanced Medicine-Medfuture, Iuliu Hatieganu University of Medicine and Pharmacy, 23 Marinescu Street, 400337 Cluj-Napoca, Romania
| | - Anca Onaciu
- Research Center for Advanced Medicine-Medfuture, Iuliu Hatieganu University of Medicine and Pharmacy, 23 Marinescu Street, 400337 Cluj-Napoca, Romania
| | - Cristian Moldovan
- Research Center for Advanced Medicine-Medfuture, Iuliu Hatieganu University of Medicine and Pharmacy, 23 Marinescu Street, 400337 Cluj-Napoca, Romania
| | - Alina-Andreea Zimta
- Research Center for Advanced Medicine-Medfuture, Iuliu Hatieganu University of Medicine and Pharmacy, 23 Marinescu Street, 400337 Cluj-Napoca, Romania
| | - Diana Gulei
- Research Center for Advanced Medicine-Medfuture, Iuliu Hatieganu University of Medicine and Pharmacy, 23 Marinescu Street, 400337 Cluj-Napoca, Romania
| | - Angelo V. Paradiso
- Oncologia Sperimentale, Istituto Tumori G Paolo II, IRCCS, 70125 Bari, Italy
| | - Vladimir Lazar
- Worldwide Innovative Network for Personalized Cancer Therapy, 94800 Villejuif, France
| | - Ioana Berindan-Neagoe
- Research Center for Advanced Medicine-Medfuture, Iuliu Hatieganu University of Medicine and Pharmacy, 23 Marinescu Street, 400337 Cluj-Napoca, Romania
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 23 Marinescu Street, 400337 Cluj-Napoca, Romania
- Department of Functional Genomics and Experimental Pathology, The Oncology Institute “Prof. Dr. Ion Chiricuta”, 34-36 Republicii Street, 400015 Cluj-Napoca, Romania
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45
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Pastorakova A, Jakubechova J, Altanerova U, Altaner C. Suicide Gene Therapy Mediated with Exosomes Produced by Mesenchymal Stem/Stromal Cells Stably Transduced with HSV Thymidine Kinase. Cancers (Basel) 2020; 12:E1096. [PMID: 32354013 PMCID: PMC7281242 DOI: 10.3390/cancers12051096] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 04/08/2020] [Accepted: 04/24/2020] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) prepared from various human tissues were stably transduced with the suicide gene herpes simplex virus thymidine kinase (HSVTK) by means of retrovirus infection. HSVTK-transduced MSCs express the suicide gene and in prodrug ganciclovir (GCV) presence induced cell death by intracellular conversion of GCV to GCV-triphosphate. The homogenous population of HSVTK-MSCs were found to release exosomes having mRNA of the suicide gene in their cargo. The exosomes were easily internalized by the tumor cells and the presence of ganciclovir caused their death in a dose-dependent manner. Efficient tumor cell killing of glioma cell lines and primary human glioblastoma cells mediated by HSVTK-MSC exosomes is reported. Exosomes produced by suicide gene transduced MSCs represent a new class of highly selective tumor cell targeted drug acting intracellular with curative potential.
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Affiliation(s)
- Andrea Pastorakova
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University in Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia
| | - Jana Jakubechova
- Stem Cell Preparation Laboratory, St. Elisabeth Cancer Institute, Heydukova 10, 812 50 Bratislava, Slovakia
| | - Ursula Altanerova
- Stem Cell Preparation Laboratory, St. Elisabeth Cancer Institute, Heydukova 10, 812 50 Bratislava, Slovakia
| | - Cestmir Altaner
- Stem Cell Preparation Laboratory, St. Elisabeth Cancer Institute, Heydukova 10, 812 50 Bratislava, Slovakia
- Biomedical Center, Cancer Research Institute, Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia
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46
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Kostadinova M, Antonov B, Kinov P, Oreshkova T, Mourdjeva M. Mesenchymal stem cells inhibit the growth of prostate carcinoma cells in a long-term cultivation. BIOTECHNOL BIOTEC EQ 2020. [DOI: 10.1080/13102818.2020.1751710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Affiliation(s)
- Milena Kostadinova
- Department of Molecular Immunology, Institute of Biology and Immunology of Reproduction “Acad. Kiril Bratanov”, Bulgarian Academy of Sciences, Sofia, Bulgaria
| | - Boris Antonov
- Department of Orthopedics and Traumatology, University Hospital “Queen Giovanna - ISUL”, Sofia, Bulgaria
| | - Plamen Kinov
- Department of Orthopedics and Traumatology, University Hospital “Queen Giovanna - ISUL”, Sofia, Bulgaria
| | - Tsvetelina Oreshkova
- Department of Molecular Immunology, Institute of Biology and Immunology of Reproduction “Acad. Kiril Bratanov”, Bulgarian Academy of Sciences, Sofia, Bulgaria
| | - Milena Mourdjeva
- Department of Molecular Immunology, Institute of Biology and Immunology of Reproduction “Acad. Kiril Bratanov”, Bulgarian Academy of Sciences, Sofia, Bulgaria
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47
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Yang L, Shi P, Zhao G, Xu J, Peng W, Zhang J, Zhang G, Wang X, Dong Z, Chen F, Cui H. Targeting cancer stem cell pathways for cancer therapy. Signal Transduct Target Ther 2020; 5:8. [PMID: 32296030 PMCID: PMC7005297 DOI: 10.1038/s41392-020-0110-5] [Citation(s) in RCA: 1170] [Impact Index Per Article: 234.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Revised: 12/15/2019] [Accepted: 12/19/2019] [Indexed: 12/18/2022] Open
Abstract
Since cancer stem cells (CSCs) were first identified in leukemia in 1994, they have been considered promising therapeutic targets for cancer therapy. These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. The biological activities of CSCs are regulated by several pluripotent transcription factors, such as OCT4, Sox2, Nanog, KLF4, and MYC. In addition, many intracellular signaling pathways, such as Wnt, NF-κB (nuclear factor-κB), Notch, Hedgehog, JAK-STAT (Janus kinase/signal transducers and activators of transcription), PI3K/AKT/mTOR (phosphoinositide 3-kinase/AKT/mammalian target of rapamycin), TGF (transforming growth factor)/SMAD, and PPAR (peroxisome proliferator-activated receptor), as well as extracellular factors, such as vascular niches, hypoxia, tumor-associated macrophages, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, extracellular matrix, and exosomes, have been shown to be very important regulators of CSCs. Molecules, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) cells have been developed to specifically target CSCs, and some of these factors are already undergoing clinical trials. This review summarizes the characterization and identification of CSCs, depicts major factors and pathways that regulate CSC development, and discusses potential targeted therapy for CSCs.
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Affiliation(s)
- Liqun Yang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Pengfei Shi
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Gaichao Zhao
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Jie Xu
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Wen Peng
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Jiayi Zhang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Guanghui Zhang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Xiaowen Wang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Zhen Dong
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Fei Chen
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, 48201, USA
| | - Hongjuan Cui
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China.
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China.
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Hadryś A, Sochanik A, McFadden G, Jazowiecka-Rakus J. Mesenchymal stem cells as carriers for systemic delivery of oncolytic viruses. Eur J Pharmacol 2020; 874:172991. [PMID: 32044323 DOI: 10.1016/j.ejphar.2020.172991] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 01/09/2020] [Accepted: 02/04/2020] [Indexed: 12/13/2022]
Abstract
Progress in genetic engineering led to the emergence of some viruses as potent anticancer therapeutics. These oncolytic viruses combine self-amplification with dual antitumor action: oncolytic (destruction of cancer cells) and immunostimulatory (eliciting acquired antitumor response against cancer epitopes). As any other viruses, they trigger antiviral response upon systemic administration. Mesenchymal stem cells are immature cells capable of self-renewing and differentiating into many cell types that belong to three germinal layers. Due to their inherent tumor tropism mesenchymal stem cells loaded with oncolytic virus can improve delivery of the therapeutic cargo to cancer sites. Shielding of oncolytic viral construct from antiviral host immune response makes these cells prospective delivery vehicles to even hard-to-reach metastatic neoplastic foci. Use of mesenchymal stem cells has been criticized by some investigators as limiting proliferative abilities of primary cells and increasing the risk of malignant transformation, as well as attenuating therapeutic responses. However, majority of preclinical studies indicate safety and efficacy of mesenchymal stem cells used as carriers of oncolytic viruses. In view of contradictory postulates, the debate continues. The review discusses mesenchymal stem cells as carriers for delivery of genetically engineered oncolytic constructs and focuses on systemic approach to oncoviral treatment of some deadly neoplasms.
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Affiliation(s)
- Agata Hadryś
- Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, Poland; Institute of Chemistry, University of Silesia, Poland.
| | - Aleksander Sochanik
- Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, Poland.
| | - Grant McFadden
- Biodesign Institute, Arizona State University, Tempe, AZ, USA.
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Therapeutic Mesenchymal Stromal Cells for Immunotherapy and for Gene and Drug Delivery. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2020; 16:204-224. [PMID: 32071924 PMCID: PMC7012781 DOI: 10.1016/j.omtm.2020.01.005] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Mesenchymal stromal cells (MSCs) possess several fairly unique properties that, when combined, make them ideally suited for cellular-based immunotherapy and as vehicles for gene and drug delivery for a wide range of diseases and disorders. Key among these are: (1) their relative ease of isolation from a variety of tissues; (2) the ability to be expanded in culture without a loss of functionality, a property that varies to some degree with tissue source; (3) they are relatively immune-inert, perhaps obviating the need for precise donor/recipient matching; (4) they possess potent immunomodulatory functions that can be tailored by so-called licensing in vitro and in vivo; (5) the efficiency with which they can be modified with viral-based vectors; and (6) their almost uncanny ability to selectively home to damaged tissues, tumors, and metastases following systemic administration. In this review, we summarize the latest research in the immunological properties of MSCs, their use as immunomodulatory/anti-inflammatory agents, methods for licensing MSCs to customize their immunological profile, and their use as vehicles for transferring both therapeutic genes in genetic disease and drugs and genes designed to destroy tumor cells.
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50
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Altaner C, Altanerova U, Jakubechova J. Intracellular acting tumor cell-targeted chemotherapy by MSC-suicide gene exosomes. Oncotarget 2019; 10:5573-5575. [PMID: 31608134 PMCID: PMC6771456 DOI: 10.18632/oncotarget.27135] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 07/22/2019] [Indexed: 01/04/2023] Open
Affiliation(s)
- Cestmir Altaner
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Center, Slovak Academy of Sciences, Bratislava, Slovakia; Stem Cell Preparation Department, St. Elisabeth Cancer Institute, Bratislava, Slovakia
| | - Ursula Altanerova
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Center, Slovak Academy of Sciences, Bratislava, Slovakia; Stem Cell Preparation Department, St. Elisabeth Cancer Institute, Bratislava, Slovakia
| | - Jana Jakubechova
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Center, Slovak Academy of Sciences, Bratislava, Slovakia; Stem Cell Preparation Department, St. Elisabeth Cancer Institute, Bratislava, Slovakia
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